Fragile X syndrome and targeted treatment trials.

PubMed

Hagerman, Randi; Lauterborn, Julie; Au, Jacky; Berry-Kravis, Elizabeth

2012-01-01

Work in recent years has revealed an abundance of possible new treatment targets for fragile X syndrome (FXS). The use of animal models, including the fragile X knockout mouse which manifests a phenotype very similar to FXS in humans, has resulted in great strides in this direction of research. The lack of Fragile X Mental Retardation Protein (FMRP) in FXS causes dysregulation and usually overexpression of a number of its target genes, which can cause imbalances of neurotransmission and deficits in synaptic plasticity. The use of metabotropic glutamate receptor (mGluR) blockers and gamma amino-butyric acid (GABA) agonists have been shown to be efficacious in reversing cellular and behavioral phenotypes, and restoring proper brain connectivity in the mouse and fly models. Proposed new pharmacological treatments and educational interventions are discussed in this chapter. In combination, these various targeted treatments show promising preliminary results in mitigating or even reversing the neurobiological abnormalities caused by loss of FMRP, with possible translational applications to other neurodevelopmental disorders including autism.

Fragile X syndrome: mechanistic insights and therapeutic avenues regarding the role of potassium channels.

PubMed

Lee, Hye Young; Jan, Lily Yeh

2012-10-01

Fragile X syndrome (FXS) is a common form of mental disability and one of the known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeats that leads to DNA methylation of the fragile X mental retardation gene 1 (FMR1) and transcriptional silencing, resulting in the absence of fragile X mental retardation protein (FMRP), an mRNA binding protein. Although it is widely known that FMRP is critical for metabotropic glutamate receptor (mGluR)-dependent long-term depression (LTD), which has provided a general theme for developing pharmacological drugs for FXS, specific downstream targets of FMRP may also be of therapeutic value. Since alterations in potassium channel expression level or activity could underlie neuronal network defects in FXS, here we describe recent findings on how these channels might be altered in mouse models of FXS and the possible therapeutic avenues for treating FXS. Copyright © 2012 Elsevier Ltd. All rights reserved.

Learning and Behavioral Deficits Associated with the Absence of the Fragile X Mental Retardation Protein: What a Fly and Mouse Model Can Teach Us

ERIC Educational Resources Information Center

Santos, Ana Rita; Kanellopoulos, Alexandros K.; Bagni, Claudia

2014-01-01

The Fragile X syndrome (FXS) is the most frequent form of inherited mental disability and is considered a monogenic cause of autism spectrum disorder. FXS is caused by a triplet expansion that inhibits the expression of the "FMR1" gene. The gene product, the Fragile X Mental Retardation Protein (FMRP), regulates mRNA metabolism in brain…

Enhanced Excitatory Connectivity and Disturbed Sound Processing in the Auditory Brainstem of Fragile X Mice.

PubMed

Garcia-Pino, Elisabet; Gessele, Nikodemus; Koch, Ursula

2017-08-02

Hypersensitivity to sounds is one of the prevalent symptoms in individuals with Fragile X syndrome (FXS). It manifests behaviorally early during development and is often used as a landmark for treatment efficacy. However, the physiological mechanisms and circuit-level alterations underlying this aberrant behavior remain poorly understood. Using the mouse model of FXS ( Fmr1 KO ), we demonstrate that functional maturation of auditory brainstem synapses is impaired in FXS. Fmr1 KO mice showed a greatly enhanced excitatory synaptic input strength in neurons of the lateral superior olive (LSO), a prominent auditory brainstem nucleus, which integrates ipsilateral excitation and contralateral inhibition to compute interaural level differences. Conversely, the glycinergic, inhibitory input properties remained unaffected. The enhanced excitation was the result of an increased number of cochlear nucleus fibers converging onto one LSO neuron, without changing individual synapse properties. Concomitantly, immunolabeling of excitatory ending markers revealed an increase in the immunolabeled area, supporting abnormally elevated excitatory input numbers. Intrinsic firing properties were only slightly enhanced. In line with the disturbed development of LSO circuitry, auditory processing was also affected in adult Fmr1 KO mice as shown with single-unit recordings of LSO neurons. These processing deficits manifested as an increase in firing rate, a broadening of the frequency response area, and a shift in the interaural level difference function of LSO neurons. Our results suggest that this aberrant synaptic development of auditory brainstem circuits might be a major underlying cause of the auditory processing deficits in FXS. SIGNIFICANCE STATEMENT Fragile X Syndrome (FXS) is the most common inheritable form of intellectual impairment, including autism. A core symptom of FXS is extreme sensitivity to loud sounds. This is one reason why individuals with FXS tend to avoid social interactions, contributing to their isolation. Here, a mouse model of FXS was used to investigate the auditory brainstem where basic sound information is first processed. Loss of the Fragile X mental retardation protein leads to excessive excitatory compared with inhibitory inputs in neurons extracting information about sound levels. Functionally, this elevated excitation results in increased firing rates, and abnormal coding of frequency and binaural sound localization cues. Imbalanced early-stage sound level processing could partially explain the auditory processing deficits in FXS. Copyright © 2017 the authors 0270-6474/17/377403-17$15.00/0.

Age-Dependent Long-Term Potentiation Deficits in the Prefrontal Cortex of the Fmr1 Knockout Mouse Model of Fragile X Syndrome.

PubMed

Martin, Henry G S; Lassalle, Olivier; Brown, Jonathan T; Manzoni, Olivier J

2016-05-01

The most common inherited monogenetic cause of intellectual disability is Fragile X syndrome (FXS). The clinical symptoms of FXS evolve with age during adulthood; however, neurophysiological data exploring this phenomenon are limited. The Fmr1 knockout (Fmr1KO) mouse models FXS, but studies in these mice of prefrontal cortex (PFC) function are underrepresented, and aging linked data are absent. We studied synaptic physiology and activity-dependent synaptic plasticity in the medial PFC of Fmr1KO mice from 2 to 12 months. In young adult Fmr1KO mice, NMDA receptor (NMDAR)-mediated long-term potentiation (LTP) is intact; however, in 12-month-old mice this LTP is impaired. In parallel, there was an increase in the AMPAR/NMDAR ratio and a concomitant decrease of synaptic NMDAR currents in 12-month-old Fmr1KO mice. We found that acute pharmacological blockade of mGlu5 receptor in 12-month-old Fmr1KO mice restored a normal AMPAR/NMDAR ratio and LTP. Taken together, the data reveal an age-dependent deficit in LTP in Fmr1KO mice, which may correlate to some of the complex age-related deficits in FXS. © The Author 2015. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development.

PubMed

Pop, Andreea S; Gomez-Mancilla, Baltazar; Neri, Giovanni; Willemsen, Rob; Gasparini, Fabrizio

2014-03-01

Fragile X syndrome (FXS) is considered the leading inherited cause of intellectual disability and autism. In FXS, the fragile X mental retardation 1 (FMR1) gene is silenced and the fragile X mental retardation protein (FMRP) is not expressed, resulting in the characteristic features of the syndrome. Despite recent advances in understanding the pathophysiology of FXS, there is still no cure for this condition; current treatment is symptomatic. Preclinical research is essential in the development of potential therapeutic agents. This review provides an overview of the preclinical evidence supporting metabotropic glutamate receptor 5 (mGluR5) antagonists as therapeutic agents for FXS. According to the mGluR theory of FXS, the absence of FMRP leads to enhanced glutamatergic signaling via mGluR5, which leads to increased protein synthesis and defects in synaptic plasticity including enhanced long-term depression. As such, efforts to develop agents that target the underlying pathophysiology of FXS have focused on mGluR5 modulation. Animal models, particularly the Fmr1 knockout mouse model, have become invaluable in exploring therapeutic approaches on an electrophysiological, behavioral, biochemical, and neuroanatomical level. Two direct approaches are currently being investigated for FXS treatment: reactivating the FMR1 gene and compensating for the lack of FMRP. The latter approach has yielded promising results, with mGluR5 antagonists showing efficacy in clinical trials. Targeting mGluR5 is a valid approach for the development of therapeutic agents that target the underlying pathophysiology of FXS. Several compounds are currently in development, with encouraging results.

Postsynaptic FMRP Promotes the Pruning of Cell-to-Cell Connections among Pyramidal Neurons in the L5A Neocortical Network

PubMed Central

Patel, Ankur B.; Loerwald, Kristofer W.; Huber, Kimberly M.

2014-01-01

Pruning of structural synapses occurs with development and learning. A deficit in pruning of cortical excitatory synapses and the resulting hyperconnectivity is hypothesized to underlie the etiology of fragile X syndrome (FXS) and related autistic disorders. However, clear evidence for pruning in neocortex and its impairment in FXS remains elusive. Using simultaneous recordings of pyramidal neurons in the layer 5A neocortical network of the wild-type (WT) mouse to observe cell-to-cell connections in isolation, we demonstrate here a specific form of “connection pruning.” Connection frequency among pyramidal neurons decreases between the third and fifth postnatal weeks, indicating a period of connection pruning. Over the same interval in the FXS model mouse, the Fmr1 knock-out (KO), connection frequency does not decrease. Therefore, connection frequency in the fifth week is higher in the Fmr1 KO compared with WT, indicating a state of hyperconnectivity. These alterations are due to postsynaptic deletion of Fmr1. At early ages (2 weeks), postsynaptic Fmr1 promoted the maturation of cell-to-cell connections, but not their number. These findings indicate that impaired connection pruning at later ages, and not an excess of connection formation, underlies the hyperconnectivity in the Fmr1 KO mouse. FMRP did not appear to regulate synapses individually, but instead regulated cell-to-cell connectivity in which groups of synapses mediating a single cell-to-cell connection are uniformly removed, retained, and matured. Although we do not link connection pruning directly to the pruning of structurally defined synapses, this study nevertheless provides an important model system for studying altered pruning in FXS. PMID:24573297

Postsynaptic FMRP promotes the pruning of cell-to-cell connections among pyramidal neurons in the L5A neocortical network.

PubMed

Patel, Ankur B; Loerwald, Kristofer W; Huber, Kimberly M; Gibson, Jay R

2014-02-26

Pruning of structural synapses occurs with development and learning. A deficit in pruning of cortical excitatory synapses and the resulting hyperconnectivity is hypothesized to underlie the etiology of fragile X syndrome (FXS) and related autistic disorders. However, clear evidence for pruning in neocortex and its impairment in FXS remains elusive. Using simultaneous recordings of pyramidal neurons in the layer 5A neocortical network of the wild-type (WT) mouse to observe cell-to-cell connections in isolation, we demonstrate here a specific form of "connection pruning." Connection frequency among pyramidal neurons decreases between the third and fifth postnatal weeks, indicating a period of connection pruning. Over the same interval in the FXS model mouse, the Fmr1 knock-out (KO), connection frequency does not decrease. Therefore, connection frequency in the fifth week is higher in the Fmr1 KO compared with WT, indicating a state of hyperconnectivity. These alterations are due to postsynaptic deletion of Fmr1. At early ages (2 weeks), postsynaptic Fmr1 promoted the maturation of cell-to-cell connections, but not their number. These findings indicate that impaired connection pruning at later ages, and not an excess of connection formation, underlies the hyperconnectivity in the Fmr1 KO mouse. FMRP did not appear to regulate synapses individually, but instead regulated cell-to-cell connectivity in which groups of synapses mediating a single cell-to-cell connection are uniformly removed, retained, and matured. Although we do not link connection pruning directly to the pruning of structurally defined synapses, this study nevertheless provides an important model system for studying altered pruning in FXS.

Metformin ameliorates core deficits in a mouse model of fragile X syndrome.

PubMed

Gantois, Ilse; Khoutorsky, Arkady; Popic, Jelena; Aguilar-Valles, Argel; Freemantle, Erika; Cao, Ruifeng; Sharma, Vijendra; Pooters, Tine; Nagpal, Anmol; Skalecka, Agnieszka; Truong, Vinh T; Wiebe, Shane; Groves, Isabelle A; Jafarnejad, Seyed Mehdi; Chapat, Clément; McCullagh, Elizabeth A; Gamache, Karine; Nader, Karim; Lacaille, Jean-Claude; Gkogkas, Christos G; Sonenberg, Nahum

2017-06-01

Fragile X syndrome (FXS) is the leading monogenic cause of autism spectrum disorders (ASD). Trinucleotide repeat expansions in FMR1 abolish FMRP expression, leading to hyperactivation of ERK and mTOR signaling upstream of mRNA translation. Here we show that metformin, the most widely used drug for type 2 diabetes, rescues core phenotypes in Fmr1 -/y mice and selectively normalizes ERK signaling, eIF4E phosphorylation and the expression of MMP-9. Thus, metformin is a potential FXS therapeutic.

eIF4E/Fmr1 double mutant mice display cognitive impairment in addition to ASD-like behaviors.

PubMed

Huynh, Thu N; Shah, Manan; Koo, So Yeon; Faraud, Kirsten S; Santini, Emanuela; Klann, Eric

2015-11-01

Autism spectrum disorder (ASD) is a group of heritable disorders with complex and unclear etiology. Classic ASD symptoms include social interaction and communication deficits as well as restricted, repetitive behaviors. In addition, ASD is often comorbid with intellectual disability. Fragile X syndrome (FXS) is the leading genetic cause of ASD, and is the most commonly inherited form of intellectual disability. Several mouse models of ASD and FXS exist, however the intellectual disability observed in ASD patients is not well modeled in mice. Using the Fmr1 knockout mouse and the eIF4E transgenic mouse, two previously characterized mouse models of fragile X syndrome and ASD, respectively, we generated the eIF4E/Fmr1 double mutant mouse. Our study shows that the eIF4E/Fmr1 double mutant mice display classic ASD behaviors, as well as cognitive dysfunction. Importantly, the learning impairments displayed by the double mutant mice spanned multiple cognitive tasks. Moreover, the eIF4E/Fmr1 double mutant mice display increased levels of basal protein synthesis. The results of our study suggest that the eIF4E/Fmr1 double mutant mouse may be a reliable model to study cognitive dysfunction in the context of ASD. Copyright © 2015 Elsevier Inc. All rights reserved.

Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome.

PubMed

Berry-Kravis, Elizabeth; Sumis, Allison; Hervey, Crystal; Nelson, Michael; Porges, Stephen W; Weng, Ning; Weiler, Ivan Jeanne; Greenough, William T

2008-08-01

In fragile X syndrome (FXS), it is hypothesized that absence of the fragile X mental retardation protein (FMRP) disrupts regulation of group 1 metabotropic glutamate receptor (mGluR and mGluR5)-dependent translation in dendrites. Lithium reduces mGluR-activated translation and reverses phenotypes in the dfxr mutant fly and fmr1 knockout mouse. This pilot add-on trial was conducted to evaluate safety and efficacy of lithium in humans with FXS. Fifteen individuals with FXS, ages 6-23, received lithium titrated to levels of 0.8-1.2 mEq/L. The primary outcome measure, the Aberrant Behavior Checklist --Community Edition (ABC-C) Irritability Subscale, secondary outcome measures (other ABC-C subscales, clinical global improvement scale (CGI), visual analog scale for behavior (VAS), Vineland Adaptive Behavior Scale (VABS)), exploratory cognitive and psychophysiological measures and an extracellular signal-regulated kinase (ERK) activation assay were administered at baseline and 2 months of treatment. Side effects were quantified with a standardized checklist and lithium level, complete blood count (CBC), thyroid stimulating hormone (TSH), and chemistry screen were done at baseline, 2 weeks, 4 weeks and 2 months. The only significant treatment-related side effects were polyuria/polydipsia (n = 7) and elevated TSH (n = 4). Although the ABC-C Irritability Subscale showed only a trend toward improvement, there was significant improvement in the Total ABC-C score (p = 0.005), VAS (p = 0.003), CGI (p = 0.002), VABS Maladaptive Behavior Subscale (p = 0.007), and RBANS List Learning (p = 0.03) and an enhanced ERK activation rate (p = 0.007). Several exploratory tasks proved too difficult for lower-functioning FXS subjects. Results from this study are consistent with results in mouse and fly models of FXS, and suggest that lithium is well-tolerated and provides functional benefits in FXS, possibly by modifying the underlying neural defect. A placebo-controlled trial of lithium in FXS is warranted.

Genetic Removal of Matrix Metalloproteinase 9 Rescues the Symptoms of Fragile X Syndrome in a Mouse Model

PubMed Central

Sidhu, Harpreet; Dansie, Lorraine E.; Hickmott, Peter W.

2014-01-01

Fmr1 knock-out (ko) mice display key features of fragile X syndrome (FXS), including delayed dendritic spine maturation and FXS-associated behaviors, such as poor socialization, obsessive-compulsive behavior, and hyperactivity. Here we provide conclusive evidence that matrix metalloproteinase-9 (MMP-9) is necessary to the development of FXS-associated defects in Fmr1 ko mice. Genetic disruption of Mmp-9 rescued key aspects of Fmr1 deficiency, including dendritic spine abnormalities, abnormal mGluR5-dependent LTD, as well as aberrant behaviors in open field and social novelty tests. Remarkably, MMP-9 deficiency also corrected non-neural features of Fmr1 deficiency—specifically macroorchidism—indicating that MMP-9 dysregulation contributes to FXS-associated abnormalities outside the CNS. Further, MMP-9 deficiency suppressed elevations of Akt, mammalian target of rapamycin, and eukaryotic translation initiation factor 4E phosphorylation seen in Fmr1 ko mice, which are also associated with other autistic spectrum disorders. These findings establish that MMP-9 is critical to the mechanisms responsible for neural and non-neural aspects of the FXS phenotype. PMID:25057190

Changes in insulin-like growth factor signaling alter phenotypes in Fragile X Mice.

PubMed

Wise, T L

2017-02-01

Fragile X syndrome (FXS) is an inherited form of intellectual disability that is usually caused by expansion of a polymorphic CGG repeat in the 5' untranslated region of the X-linked FMR1 gene, which leads to hypermethylation and transcriptional silencing. Two non-neurological phenotypes of FXS are enlarged testes and connective tissue dysplasia, which could be caused by alterations in a growth factor signaling pathway. FXS patients also frequently have autistic-like symptoms, suggesting that the signaling pathways affected in FXS may overlap with those affected in autism. Identifying these pathways is important for both understanding the effects of FMR1 inactivation and developing treatments for both FXS and autism. Here we show that decreasing the levels of the insulin-like growth factor (Igf) receptor 1 corrects a number of phenotypes in the mouse model of FXS, including macro-orchidism, and that increasing the levels of IGF2 exacerbates the seizure susceptibility phenotype. These results suggest that the pathways altered by the loss of the FMR1-encoded protein (FMRP) may overlap with the pathways affected by changes in Igf signaling or that one or more of the proteins that play a role in Igf signaling could interact with FMRP. They also indicate a new set of potential targets for drug treatment of FXS and autism spectrum disorders. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

Altered cerebral protein synthesis in fragile X syndrome: studies in human subjects and knockout mice

PubMed Central

Qin, Mei; Schmidt, Kathleen C; Zametkin, Alan J; Bishu, Shrinivas; Horowitz, Lisa M; Burlin, Thomas V; Xia, Zengyan; Huang, Tianjiang; Quezado, Zenaide M; Smith, Carolyn Beebe

2013-01-01

Dysregulated protein synthesis is thought to be a core phenotype of fragile X syndrome (FXS). In a mouse model (Fmr1 knockout (KO)) of FXS, rates of cerebral protein synthesis (rCPS) are increased in selective brain regions. We hypothesized that rCPS are also increased in FXS subjects. We measured rCPS with the ℒ-[1-11C]leucine positron emission tomography (PET) method in whole brain and 10 regions in 15 FXS subjects who, because of their impairments, were studied under deep sedation with propofol. We compared results with those of 12 age-matched controls studied both awake and sedated. In controls, we found no differences in rCPS between awake and propofol sedation. Contrary to our hypothesis, FXS subjects under propofol sedation had reduced rCPS in whole brain, cerebellum, and cortex compared with sedated controls. To investigate whether propofol could have a disparate effect in FXS subjects masking usually elevated rCPS, we measured rCPS in C57Bl/6 wild-type (WT) and KO mice awake or under propofol sedation. Propofol decreased rCPS substantially in most regions examined in KO mice, but in WT mice caused few discrete changes. Propofol acts by decreasing neuronal activity either directly or by increasing inhibitory synaptic activity. Our results suggest that changes in synaptic signaling can correct increased rCPS in FXS. PMID:23299245

Electrocortical changes associated with minocycline treatment in fragile X syndrome.

PubMed

Schneider, Andrea; Leigh, Mary Jacena; Adams, Patrick; Nanakul, Rawi; Chechi, Tasleem; Olichney, John; Hagerman, Randi; Hessl, David

2013-10-01

Minocycline normalizes synaptic connections and behavior in the knockout mouse model of fragile X syndrome (FXS). Human-targeted treatment trials with minocycline have shown benefits in behavioral measures and parent reports. Event-related potentials (ERPs) may provide a sensitive method of monitoring treatment response and changes in coordinated brain activity. Measurement of electrocortical changes due to minocycline was done in a double-blind, placebo-controlled crossover treatment trial in children with FXS. Children with FXS (Meanage 10.5 years) were randomized to minocycline or placebo treatment for 3 months then changed to the other treatment for 3 months. The minocycline dosage ranged from 25-100 mg daily, based on weight. Twelve individuals with FXS (eight male, four female) completed ERP studies using a passive auditory oddball paradigm. Current source density (CSD) and ERP analysis at baseline showed high-amplitude, long-latency components over temporal regions. After 3 months of treatment with minocycline, the temporal N1 and P2 amplitudes were significantly reduced compared with placebo. There was a significant amplitude increase of the central P2 component on minocycline. Electrocortical habituation to auditory stimuli improved with minocycline treatment. Our study demonstrated improvements of the ERP in children with FXS treated with minocycline, and the potential feasibility and sensitivity of ERPs as a cognitive biomarker in FXS treatment trials.

Changes in sensitivity of reward and motor behavior to dopaminergic, glutamatergic, and cholinergic drugs in a mouse model of fragile X syndrome.

PubMed

Fish, Eric W; Krouse, Michael C; Stringfield, Sierra J; Diberto, Jeffrey F; Robinson, J Elliott; Malanga, C J

2013-01-01

Fragile X syndrome (FXS) is a leading cause of intellectual disability. FXS is caused by loss of function of the FMR1 gene, and mice in which Fmr1 has been inactivated have been used extensively as a preclinical model for FXS. We investigated the behavioral pharmacology of drugs acting through dopaminergic, glutamatergic, and cholinergic systems in fragile X (Fmr1 (-/Y)) mice with intracranial self-stimulation (ICSS) and locomotor activity measurements. We also measured brain expression of tyrosine hydroxylase (TH), the rate-limiting enzyme in dopamine biosynthesis. Fmr1 (-/Y) mice were more sensitive than wild type mice to the rewarding effects of cocaine, but less sensitive to its locomotor stimulating effects. Anhedonic but not motor depressant effects of the atypical neuroleptic, aripiprazole, were reduced in Fmr1 (-/Y) mice. The mGluR5-selective antagonist, 6-methyl-2-(phenylethynyl)pyridine (MPEP), was more rewarding and the preferential M1 antagonist, trihexyphenidyl, was less rewarding in Fmr1 (-/Y) than wild type mice. Motor stimulation by MPEP was unchanged, but stimulation by trihexyphenidyl was markedly increased, in Fmr1 (-/Y) mice. Numbers of midbrain TH+ neurons in the ventral tegmental area were unchanged, but were lower in the substantia nigra of Fmr1 (-/Y) mice, although no changes in TH levels were found in their forebrain targets. The data are discussed in the context of known changes in the synaptic physiology and pharmacology of limbic motor systems in the Fmr1 (-/Y) mouse model. Preclinical findings suggest that drugs acting through multiple neurotransmitter systems may be necessary to fully address abnormal behaviors in individuals with FXS.

Effects of stimulus salience on touchscreen serial reversal learning in a mouse model of fragile X syndrome

PubMed Central

Dickson, Price E.; Corkill, Beau; McKimm, Eric; Miller, Mellessa M.; Calton, Michele A.; Goldowitz, Daniel; Blaha, Charles D.; Mittleman, Guy

2013-01-01

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability in males and the most common genetic cause of autism. Although executive dysfunction is consistently found in humans with FXS, evidence of executive dysfunction in Fmr1 KO mice, a mouse model of FXS, has been inconsistent. One possible explanation for this is that executive dysfunction in Fmr1 KO mice, similar to humans with FXS, is only evident when cognitive demands are high. Using touchscreen operant conditioning chambers, male Fmr1 KO mice and their male wildtype littermates were tested on the acquisition of a pairwise visual discrimination followed by four serial reversals of the response rule. We assessed reversal learning performance under two different conditions. In the first, the correct stimulus was salient and the incorrect stimulus was non-salient. In the second and more challenging condition, the incorrect stimulus was salient and the correct stimulus was non-salient; this increased cognitive load by introducing conflict between sensory-driven (i.e., bottom-up) and task-dependent (i.e., top-down) signals. Fmr1 KOs displayed two distinct impairments relative to wildtype littermates. First, Fmr1 KOs committed significantly more learning-type errors during the second reversal stage, but only under high cognitive load. Second, during the first reversal stage, Fmr1 KOs committed significantly more attempts to collect a reward during the timeout following an incorrect response. These findings indicate that Fmr1 KO mice display executive dysfunction that, in some cases, is only evident under high cognitive load. PMID:23747611

Early social enrichment rescues adult behavioral and brain abnormalities in a mouse model of fragile X syndrome.

PubMed

Oddi, Diego; Subashi, Enejda; Middei, Silvia; Bellocchio, Luigi; Lemaire-Mayo, Valerie; Guzmán, Manuel; Crusio, Wim E; D'Amato, Francesca R; Pietropaolo, Susanna

2015-03-13

Converging lines of evidence support the use of environmental stimulation to ameliorate the symptoms of a variety of neurodevelopmental disorders. Applying these interventions at very early ages is critical to achieve a marked reduction of the pathological phenotypes. Here we evaluated the impact of early social enrichment in Fmr1-KO mice, a genetic mouse model of fragile X syndrome (FXS), a major developmental disorder and the most frequent monogenic cause of autism. Enrichment was achieved by providing male KO pups and their WT littermates with enhanced social stimulation, housing them from birth until weaning with the mother and an additional nonlactating female. At adulthood they were tested for locomotor, social, and cognitive abilities; furthermore, dendritic alterations were assessed in the hippocampus and amygdala, two brain regions known to be involved in the control of the examined behaviors and affected by spine pathology in Fmr1-KOs. Enrichment rescued the behavioral FXS-like deficits displayed in adulthood by Fmr1-KO mice, that is, hyperactivity, reduced social interactions, and cognitive deficits. Early social enrichment also eliminated the abnormalities shown by adult KO mice in the morphology of hippocampal and amygdala dendritic spines, namely an enhanced density of immature vs mature types. Importantly, enrichment did not induce neurobehavioral changes in WT mice, thus supporting specific effects on FXS-like pathology. These findings show that early environmental stimulation has profound and long-term beneficial effects on the pathological FXS phenotype, thereby encouraging the use of nonpharmacological interventions for the treatment of this and perhaps other neurodevelopmental diseases.

Neural synchronization deficits linked to cortical hyper-excitability and auditory hypersensitivity in fragile X syndrome.

PubMed

Ethridge, Lauren E; White, Stormi P; Mosconi, Matthew W; Wang, Jun; Pedapati, Ernest V; Erickson, Craig A; Byerly, Matthew J; Sweeney, John A

2017-01-01

Studies in the fmr1 KO mouse demonstrate hyper-excitability and increased high-frequency neuronal activity in sensory cortex. These abnormalities may contribute to prominent and distressing sensory hypersensitivities in patients with fragile X syndrome (FXS). The current study investigated functional properties of auditory cortex using a sensory entrainment task in FXS. EEG recordings were obtained from 17 adolescents and adults with FXS and 17 age- and sex-matched healthy controls. Participants heard an auditory chirp stimulus generated using a 1000-Hz tone that was amplitude modulated by a sinusoid linearly increasing in frequency from 0-100 Hz over 2 s. Single trial time-frequency analyses revealed decreased gamma band phase-locking to the chirp stimulus in FXS, which was strongly coupled with broadband increases in gamma power. Abnormalities in gamma phase-locking and power were also associated with theta-gamma amplitude-amplitude coupling during the pre-stimulus period and with parent reports of heightened sensory sensitivities and social communication deficits. This represents the first demonstration of neural entrainment alterations in FXS patients and suggests that fast-spiking interneurons regulating synchronous high-frequency neural activity have reduced functionality. This reduced ability to synchronize high-frequency neural activity was related to the total power of background gamma band activity. These observations extend findings from fmr1 KO models of FXS, characterize a core pathophysiological aspect of FXS, and may provide a translational biomarker strategy for evaluating promising therapeutics.

Synaptic vesicle dynamic changes in a model of fragile X.

PubMed

Broek, Jantine A C; Lin, Zhanmin; de Gruiter, H Martijn; van 't Spijker, Heleen; Haasdijk, Elize D; Cox, David; Ozcan, Sureyya; van Cappellen, Gert W A; Houtsmuller, Adriaan B; Willemsen, Rob; de Zeeuw, Chris I; Bahn, Sabine

2016-01-01

Fragile X syndrome (FXS) is a single-gene disorder that is the most common heritable cause of intellectual disability and the most frequent monogenic cause of autism spectrum disorders (ASD). FXS is caused by an expansion of trinucleotide repeats in the promoter region of the fragile X mental retardation gene (Fmr1). This leads to a lack of fragile X mental retardation protein (FMRP), which regulates translation of a wide range of messenger RNAs (mRNAs). The extent of expression level alterations of synaptic proteins affected by FMRP loss and their consequences on synaptic dynamics in FXS has not been fully investigated. Here, we used an Fmr1 knockout (KO) mouse model to investigate the molecular mechanisms underlying FXS by monitoring protein expression changes using shotgun label-free liquid-chromatography mass spectrometry (LC-MS(E)) in brain tissue and synaptosome fractions. FXS-associated candidate proteins were validated using selected reaction monitoring (SRM) in synaptosome fractions for targeted protein quantification. Furthermore, functional alterations in synaptic release and dynamics were evaluated using live-cell imaging, and interpretation of synaptic dynamics differences was investigated using electron microscopy. Key findings relate to altered levels of proteins involved in GABA-signalling, especially in the cerebellum. Further exploration using microscopy studies found reduced synaptic vesicle unloading of hippocampal neurons and increased vesicle unloading in cerebellar neurons, which suggests a general decrease of synaptic transmission. Our findings suggest that FMRP is a regulator of synaptic vesicle dynamics, which supports the role of FMRP in presynaptic functions. Taken together, these studies provide novel insights into the molecular changes associated with FXS.

Lithium ameliorates altered glycogen synthase kinase-3 and behavior in a mouse model of fragile X syndrome.

PubMed

Yuskaitis, Christopher J; Mines, Marjelo A; King, Margaret K; Sweatt, J David; Miller, Courtney A; Jope, Richard S

2010-02-15

Fragile X syndrome (FXS), the most common form of inherited mental retardation and a genetic cause of autism, results from mutated fragile X mental retardation-1 (Fmr1). This study examined the effects on glycogen synthase kinase-3 (GSK3) of treatment with a metabotropic glutamate receptor (mGluR) antagonist, MPEP, and the GSK3 inhibitor, lithium, in C57Bl/6 Fmr1 knockout mice. Increased mGluR signaling may contribute to the pathology of FXS, and the mGluR5 antagonist MPEP increased inhibitory serine-phosphorylation of brain GSK3 selectively in Fmr1 knockout mice but not in wild-type mice. Inhibitory serine-phosphorylation of GSK3 was lower in Fmr1 knockout, than wild-type, mouse brain regions and was increased by acute or chronic lithium treatment, which also increased hippocampal brain-derived neurotrophic factor levels. Fmr1 knockout mice displayed alterations in open-field activity, elevated plus-maze, and passive avoidance, and these differences were ameliorated by chronic lithium treatment. These findings support the hypothesis that impaired inhibition of GSK3 contributes to the pathogenesis of FXS and support GSK3 as a potential therapeutic target.

Characterization of ultrasonic vocalizations of Fragile X mice.

PubMed

Belagodu, Amogh P; Johnson, Aaron M; Galvez, Roberto

2016-09-01

Fragile X Syndrome (FXS) is the leading form of inherited intellectual disability. It is caused by the transcriptional silencing of FMR1, the gene which codes for the Fragile X Mental Retardation Protein (FMRP). Patients who have FXS exhibit numerous behavioral and cognitive impairments, such as attention-deficit/hyperactivity disorder, obsessive compulsive disorder, and autistic-like behaviors. In addition to these behavioral abnormalities, FXS patients have also been shown to exhibit various deficits in communication such as abnormal sentence structures, increased utterances, repetition of sounds and words, and reduced articulation. These deficits can dramatically hinder communication for FXS patients, exacerbating learning and cognition impairments while decreasing their quality of life. To examine the biological underpinnings of these communication abnormalities, studies have used a mouse model of the Fragile X Syndrome; however, these vocalization studies have resulted in inconsistent findings that often do not correlate with abnormalities observed in FXS patients. Interestingly, a detailed examination of frequency modulated vocalizations that are believed to be a better assessment of rodent communication has never been conducted. The following study used courtship separation to conduct a detailed examination of frequency modulated ultrasonic vocalizations (USV) in FXS mice. Our analyses of frequency modulated USVs demonstrated that adult FXS mice exhibited longer phrases and more motifs. Phrases are vocalizations consisting of multiple frequency modulated ultrasonic vocalizations, while motifs are repeated frequency modulated USV patterns. Fragile X mice had a higher proportion of "u" syllables in all USVs and phrases while their wildtype counterparts preferred isolated "h" syllables. Although the specific importance of these syllables towards communication deficits still needs to be evaluated, these findings in production of USVs are consistent with the repetitive and perseverative speech patterns observed in FXS patients. This study demonstrates that FXS mice can be used to study the underlying biological mechanism(s) mediating FXS vocalization abnormalities. Copyright © 2016 Elsevier B.V. All rights reserved.

Modulation of the GABAergic pathway for the treatment of fragile X syndrome.

PubMed

Lozano, Reymundo; Hare, Emma B; Hagerman, Randi J

2014-01-01

Fragile X syndrome (FXS) is the most common genetic cause of intellectual disability and the most common single-gene cause of autism. It is caused by mutations on the fragile X mental retardation gene (FMR1) and lack of fragile X mental retardation protein, which in turn, leads to decreased inhibition of translation of many synaptic proteins. The metabotropic glutamate receptor (mGluR) hypothesis states that the neurological deficits in individuals with FXS are due mainly to downstream consequences of overstimulation of the mGluR pathway. The main efforts have focused on mGluR5 targeted treatments; however, investigation on the gamma-aminobutyric acid (GABA) system and its potential as a targeted treatment is less emphasized. The fragile X mouse models (Fmr1-knock out) show decreased GABA subunit receptors, decreased synthesis of GABA, increased catabolism of GABA, and overall decreased GABAergic input in many regions of the brain. Consequences of the reduced GABAergic input in FXS include oversensitivity to sensory stimuli, seizures, and anxiety. Deficits in the GABA receptors in different regions of the brain are associated with behavioral and attentional processing deficits linked to anxiety and autistic behaviors. The understanding of the neurobiology of FXS has led to the development of targeted treatments for the core behavioral features of FXS, which include social deficits, inattention, and anxiety. These symptoms are also observed in individuals with autism and other neurodevelopmental disorders, therefore the targeted treatments for FXS are leading the way in the treatment of other neurodevelopmental syndromes and autism. The GABAergic system in FXS represents a target for new treatments. Herein, we discuss the animal and human trials of GABAergic treatment in FXS. Arbaclofen and ganaxolone have been used in individuals with FXS. Other potential GABAergic treatments, such as riluzole, gaboxadol, tiagabine, and vigabatrin, will be also discussed. Further studies are needed to determine the safety and efficacy of GABAergic treatments for FXS.

Treatment of the psychiatric problems associated with fragile X syndrome.

PubMed

Hagerman, Randi J; Polussa, Jonathan

2015-03-01

This work reviews recent research regarding treatment of fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder. The phenotype includes anxiety linked to sensory hyperarousal, hyperactivity, and attentional problems consistent with attention deficit hyperactivity disorder and social deficits leading to autism spectrum disorder in 60% of boys and 25% of girls with FXS. Multiple targeted treatments for FXS have rescued the phenotype of the fmr1 knockout mouse, but few have been beneficial to patients with FXS. The failure of the metabotropic glutamate receptor 5 antagonists falls on the heels of the failure of Arbaclofen's efficacy in children and adults with autism or FXS. In contrast, efficacy has been demonstrated in a controlled trial of minocycline in children with FXS. Minocycline lowers the abnormally elevated levels of matrix metalloproteinase 9 in FXS. Acamprosate and lovastatin have been beneficial in open-label trials in FXS. The first 5 years of life may be the most efficacious time for intervention when combined with behavioral and/or educational interventions. Minocycline, acamprosate, lovastatin, and sertraline are treatments that can be currently prescribed and have shown benefit in children with FXS. Use of combined medical and behavioral interventions will likely be most efficacious for the treatment of FXS.

R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome

PubMed Central

Qin, Mei; Huang, Tianjian; Kader, Michael; Krych, Leland; Xia, Zengyan; Burlin, Thomas; Zeidler, Zachary; Zhao, Tingrui

2015-01-01

Background: Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates. Methods: To answer this question, we measured regional rates of cerebral protein synthesis in vivo with the L-[1-14C]leucine method in vehicle- and R-baclofen–treated wildtype and Fmr1 KO mice. We further probed signaling pathways involved in the regulation of protein synthesis. Results: Acute R-baclofen administration corrected elevated protein synthesis and reduced deficits on a test of social behavior in adult Fmr1 KO mice. It also suppressed activity of the mammalian target of rapamycin pathway, particularly in synaptosome-enriched fractions, but it had no effect on extracellular-regulated kinase 1/2 activity. Ninety min after R-baclofen treatment, we observed an increase in metabotropic glutamate receptor 5 expression in the frontal cortex, a finding that may shed light on the tolerance observed in human studies with this drug. Conclusions: Our results suggest that treatment via activation of the GABA (GABA receptor subtype B) system warrants further study in patients with FXS. PMID:25820841

High MMP-9 activity levels in fragile X syndrome are lowered by minocycline.

PubMed

Dziembowska, Magdalena; Pretto, Dalyir I; Janusz, Aleksandra; Kaczmarek, Leszek; Leigh, Mary Jacena; Gabriel, Nielsen; Durbin-Johnson, Blythe; Hagerman, Randi J; Tassone, Flora

2013-08-01

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by lack of the FMR1 protein, FMRP, a translational repressor. Its absence leads to up-regulation of locally translated proteins involved in synaptic transmission and plasticity, including the matrix metalloproteinase-9 (MMP-9). In the Fmr1 knock-out (KO), a mouse model of FXS, an abnormal elevated expression of MMP-9 in the brain was pharmacologically down-regulated after treatment with the tetracycline derivative minocycline. Moreover, the rescue of immature dendritic spine morphology and a significant improvement of abnormal behavior were associated with down-regulation of MMP-9. Here, we report on high plasma activity of MMP-9 in individuals with FXS. In addition, we investigate MMP-9 changes in patients with FXS who have gone through a minocycline controlled clinical trial and correlate MMP-9 activity to clinical observations. The results of this study suggest that, in humans, activity levels of MMP-9 are lowered by minocycline and that, in some cases, changes in MMP-9 activity are positively associated with improvement based on clinical measures. Copyright © 2013 Wiley Periodicals, Inc.

Paradoxical effect of baclofen on social behavior in the fragile X syndrome mouse model.

PubMed

Zeidler, Shimriet; Pop, Andreea S; Jaafar, Israa A; de Boer, Helen; Buijsen, Ronald A M; de Esch, Celine E F; Nieuwenhuizen-Bakker, Ingeborg; Hukema, Renate K; Willemsen, Rob

2018-06-01

Fragile X syndrome (FXS) is a common monogenetic cause of intellectual disability, autism spectrum features, and a broad range of other psychiatric and medical problems. FXS is caused by the lack of the fragile X mental retardation protein (FMRP), a translational regulator of specific mRNAs at the postsynaptic compartment. The absence of FMRP leads to aberrant synaptic plasticity, which is believed to be caused by an imbalance in excitatory and inhibitory network functioning of the synapse. Evidence from studies in mice demonstrates that GABA, the major inhibitory neurotransmitter in the brain, and its receptors, is involved in the pathogenesis of FXS. Moreover, several FXS phenotypes, including social behavior deficits, could be corrected in Fmr1 KO mice after acute treatment with GABA B agonists. As FXS would probably require a lifelong treatment, we investigated the effect of chronic treatment with the GABA B agonist baclofen on social behavior in Fmr1 KO mice on two behavioral paradigms for social behavior: the automated tube test and the three-chamber sociability test. Unexpectedly, chronic baclofen treatment resulted in worsening of the FXS phenotypes in these behavior tests. Strikingly, baclofen treatment also affected wild-type animals in both behavioral tests, inducing a phenotype similar to that of untreated Fmr1 KO mice. Altogether, the disappointing results of recent clinical trials with the R-baclofen enantiomer arbaclofen and our current results indicate that baclofen should be reconsidered and further evaluated before its application in targeted treatment for FXS. © 2018 The Authors. Brain and Behavior published by Wiley Periodicals, Inc.

Behavioral effects of chronic stress in the Fmr1 mouse model for fragile X syndrome.

PubMed

Lemaire-Mayo, Valerie; Subashi, Enejda; Henkous, Nadia; Beracochea, Daniel; Pietropaolo, Susanna

2017-03-01

Fragile X Syndrome (FXS) is a pervasive developmental disorder due to a mutation in the FMR1 X-linked gene. Despite its clear genetic cause, the expression of FXS symptoms is known to be modulated by environmental factors, including stress. Furthermore, several studies have shown disturbances in stress regulatory systems in FXS patients and Fmr1 mice. These studies have mostly focused on the hormonal responses to stress, using the acute exposure to a single type of stressor. Hence, little is known about the behavioral effects of stress in FXS, and the importance of the nature of the stressing procedure, especially in the context of a repeated exposure that more closely resembles real life conditions. Here we evaluated the effects of chronic exposure to different types of stress (i.e., either repeated restraint or unpredictable stress) on the behavioral phenotype of adult Fmr1 mice. Our results demonstrated that chronic stress induced deficits in social interaction and working memory only in WT mice and the impact of stress depended on the type of stressors and the specific behavior tested. Our data suggest that the behavioral sensitivity to stress is dramatically reduced in FXS, opening new views on the impact of gene-environment interactions in this pathology. Copyright © 2016. Published by Elsevier B.V.

Analysis of FMR1 deletion in a subpopulation of post-mitotic neurons in mouse cortex and hippocampus.

PubMed

Amiri, Anahita; Sanchez-Ortiz, Efrain; Cho, Woosung; Birnbaum, Shari G; Xu, Jing; McKay, Renée M; Parada, Luis F

2014-02-01

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and the leading cause of autism. FXS is caused by mutation in a single gene, FMR1, which encodes an RNA-binding protein FMRP. FMRP is highly expressed in neurons and is hypothesized to have a role in synaptic structure, function, and plasticity by regulating mRNAs that encode pre- and post-synaptic proteins. Fmr1 knockout (KO) mice have been used as a model to study FXS. These mice have been reported to show a great degree of phenotypic variability based on the genetic background, environmental signals, and experimental methods. In this study, we sought to restrict FMRP deletion to two brain regions that have been implicated in FXS and autism. We show that ablating Fmr1 in differentiated neurons of hippocampus and cortex results in dendritic alterations and changes in synaptic marker intensity that are brain region specific. In our conditional mutant mice, FMRP-deleted neurons have activated AKT-mTOR pathway signaling in hippocampus but display no apparent behavioral phenotypes. These results highlight the importance of identifying additional factors that interact with Fmr1 to develop FXS. © 2013 International Society for Autism Research, Wiley Periodicals, Inc.

Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome.

PubMed

Olmos-Serrano, Jose Luis; Paluszkiewicz, Scott M; Martin, Brandon S; Kaufmann, Walter E; Corbin, Joshua G; Huntsman, Molly M

2010-07-21

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by variable cognitive impairment and behavioral disturbances such as exaggerated fear, anxiety and gaze avoidance. Consistent with this, findings from human brain imaging studies suggest dysfunction of the amygdala. Underlying alterations in amygdala synaptic function in the Fmr1 knock-out (KO) mouse model of FXS, however, remain largely unexplored. Utilizing a combination of approaches, we uncover profound alterations in inhibitory neurotransmission in the amygdala of Fmr1 KO mice. We demonstrate a dramatic reduction in the frequency and amplitude of phasic IPSCs, tonic inhibitory currents, as well as in the number of inhibitory synapses in Fmr1 KO mice. Furthermore, we observe significant alterations in GABA availability, both intracellularly and at the synaptic cleft. Together, these findings identify abnormalities in basal and action potential-dependent inhibitory neurotransmission. Additionally, we reveal a significant neuronal hyperexcitability in principal neurons of the amygdala in Fmr1 KO mice, which is strikingly rescued by pharmacological augmentation of tonic inhibitory tone using the GABA agonist gaboxadol (THIP). Thus, our study reveals relevant inhibitory synaptic abnormalities in the amygdala in the Fmr1 KO brain and supports the notion that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach toward correcting amygdala-based symptoms in FXS.

Defective GABAergic neurotransmision and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of Fragile X Syndrome

PubMed Central

Olmos-Serrano, Jose Luis; Paluszkiewicz, Scott M.; Martin, Brandon S.; Kaufmann, Walter E.; Corbin, Joshua G.; Huntsman, Molly M.

2010-01-01

Fragile X Syndrome (FXS) is a neurodevelopmental disorder characterized by variable cognitive impairment and behavioural disturbances such as exaggerated fear, anxiety and gaze avoidance. Consistent with this, findings from human brain imaging studies suggest dysfunction of the amygdala. Underlying alterations in amygdala synaptic function in the Fmr1 knockout (KO) mouse model of FXS, however, remain largely unexplored. Utilizing a combination of approaches, we uncover profound alterations in inhibitory neurotransmission in the amygdala of Fmr1 KO mice. We demonstrate a dramatic reduction in the frequency and amplitude of phasic inhibitory postsynaptic currents (IPSCs), tonic inhibitory currents, as well as in the number of inhibitory synapses in Fmr1 KO mice. Furthermore, we observe significant alterations in GABA availability, both intracellularly and at the synaptic cleft. Together, these findings identify abnormalities in basal and action potential-dependent inhibitory neurotransmission. Additionally, we reveal a significant neuronal hyperexcitability in principal neurons of the amygdala in Fmr1 KO mice, which is strikingly rescued by pharmacological augmentation of tonic inhibitory tone using the GABA agonist, gaboxadol (THIP). Thus, our study reveals relevant inhibitory synaptic abnormalities in the amygdala in the Fmr1 KO brain and supports the notion that pharmacological approaches targeting the GABAergic system may be a viable therapeutic approach toward correcting amygdala-based symptoms in FXS. PMID:20660275

Somatosensory map expansion and altered processing of tactile inputs in a mouse model of fragile X syndrome.

PubMed

Juczewski, Konrad; von Richthofen, Helen; Bagni, Claudia; Celikel, Tansu; Fisone, Gilberto; Krieger, Patrik

2016-12-01

Fragile X syndrome (FXS) is a common inherited form of intellectual disability caused by the absence or reduction of the fragile X mental retardation protein (FMRP) encoded by the FMR1 gene. In humans, one symptom of FXS is hypersensitivity to sensory stimuli, including touch. We used a mouse model of FXS (Fmr1 KO) to study sensory processing of tactile information conveyed via the whisker system. In vivo electrophysiological recordings in somatosensory barrel cortex showed layer-specific broadening of the receptive fields at the level of layer 2/3 but not layer 4, in response to whisker stimulation. Furthermore, the encoding of tactile stimuli at different frequencies was severely affected in layer 2/3. The behavioral effect of this broadening of the receptive fields was tested in the gap-crossing task, a whisker-dependent behavioral paradigm. In this task the Fmr1 KO mice showed differences in the number of whisker contacts with platforms, decrease in the whisker sampling duration and reduction in the whisker touch-time while performing the task. We propose that the increased excitability in the somatosensory barrel cortex upon whisker stimulation may contribute to changes in the whisking strategy as well as to other observed behavioral phenotypes related to tactile processing in Fmr1 KO mice. Copyright © 2016 Elsevier Inc. All rights reserved.

Dysregulated NMDA-Receptor Signaling Inhibits Long-Term Depression in a Mouse Model of Fragile X Syndrome.

PubMed

Toft, Anna Karina Hugger; Lundbye, Camilla Johanne; Banke, Tue G

2016-09-21

Fragile X syndrome (FXS) is a neurodevelopmental disease. It is one of the leading monogenic causes of intellectual disability among boys with most also displaying autism spectrum disorder traits. Here we investigated the role of NMDA receptors on mGluR-dependent long-term depression (mGluR-LTD), a key biomarker in the disease, at four different developmental stages. First, we applied the mGluR agonist 3,5-dihydroxyphenylglycine in the absence or presence of the NMDAR blocker, APV, hereby unmasking the NMDAR component in this process. As expected, in the presence of APV, we found more LTD in the mouse KO than in WT. This, however, was only observed in the p30-60 age group. At all other age groups tested, mGluR-LTD was almost identical between KO and WT. Interestingly, at p60, in the absence of APV, no or very little LTD was found in KO that was completely restored by application of APV. This suggests that the underlying cause of the enhanced mGluR-LTD in KO (at p30) is caused by dysregulated NMDAR signaling. To investigate this further, we next used NMDAR-subunit-specific antagonists. Inhibition of GluN2B, but not GluN2A, blocked mGluR-LTD only in WT. This was in contrast in the KO where blocking GluN2B rescued mGluR-LTD, suggesting GluN2B-containing NMDARs in the KO are hyperactive. Thus, these findings suggest strong involvement of GluN2B-containing-NMDARs in the pathophysiology of FXS and highlight a potential path for treatment for the disease. There is currently no cure for fragile X, although medications targeting specific FXS symptoms do exist. The FXS animal model, the Fmr1 knock-out mouse, has demonstrated an increased mGluR5-mediated long-term depression (LTD) leading to several clinical trials of mGluR5 inhibitors/modulators, yet all have failed. In addition, surprisingly little information exists about the possible role of other ion channels/receptors, including NMDA receptors (NMDAR), in mGluR-LTD. Here we focus on NMDARs and their regulation of mGluR-mediated LTD at different developmental stages using several different NMDAR blockers/antagonists. Our findings suggest dysregulated NMDARs in the pathophysiology of FXS leading to altered mGluR-mediated LTD. Together, these data will help to develop new drug candidates that could lead to reversal of the FXS phenotype. Copyright © 2016 the authors 0270-6474/16/369817-11$15.00/0.

Disrupted mGluR5-Homer scaffolds mediate abnormal mGluR5 signaling, circuit function and behavior in a mouse model of Fragile X Syndrome

PubMed Central

Ronesi, Jennifer A.; Collins, Katie A.; Hays, Seth A.; Tsai, Nien-Pei; Guo, Weirui; Birnbaum, Shari G.; Hu, Jia-Hua; Worley, Paul F.; Gibson, Jay R.; Huber, Kimberly M.

2012-01-01

Enhanced mGluR5 function is causally associated with the pathophysiology of Fragile X Syndrome (FXS), a leading inherited cause of intellectual disability and autism. Here we provide evidence that altered mGluR5-Homer scaffolds contribute to mGluR5 dysfunction and phenotypes in the FXS mouse model, Fmr1 KO. In Fmr1 KO mice mGluR5 is less associated with long Homer isoforms, but more associated with the short Homer1a. Genetic deletion of Homer1a restores mGluR5- long Homer scaffolds and corrects multiple phenotypes in Fmr1 KO mice including altered mGluR5 signaling, neocortical circuit dysfunction, and behavior. Acute, peptide-mediated disruption of mGluR5-Homer scaffolds in wildtype mice mimics many Fmr1 KO phenotypes. In contrast, Homer1a deletion does not rescue altered mGluR-dependent long-term synaptic depression or translational control of FMRP target mRNAs. Our findings reveal novel functions for mGluR5-Homer interactions in the brain and delineate distinct mechanisms of mGluR5 dysfunction in a mouse model of cognitive dysfunction and autism. PMID:22267161

Fragile X: leading the way for targeted treatments in autism.

PubMed

Wang, Lulu W; Berry-Kravis, Elizabeth; Hagerman, Randi J

2010-07-01

Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5' end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55-200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2-3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150-200), lowered levels of FMRP also occur. (c) 2010 The American Society for Experimental NeuroTherapeutics, Inc. Published by Elsevier Inc. All rights reserved.

Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome

PubMed Central

Lovelace, Jonathan W.; Wen, Teresa H.; Reinhard, Sarah; Hsu, Mike S.; Sidhu, Harpreet; Ethell, Iryna M.; Binder, Devin K.; Razak, Khaleel A.

2016-01-01

Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase −9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS. PMID:26850918

Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders

PubMed Central

Francis, S.M.; Sagar, A.; Levin-Decanini, T.; Liu, W.; Carter, C.S.; Jacob, S.

2015-01-01

Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader–Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD. PMID:24462936

Of Men and Mice: Modeling the Fragile X Syndrome

PubMed Central

Dahlhaus, Regina

2018-01-01

The Fragile X Syndrome (FXS) is one of the most common forms of inherited intellectual disability in all human societies. Caused by the transcriptional silencing of a single gene, the fragile x mental retardation gene FMR1, FXS is characterized by a variety of symptoms, which range from mental disabilities to autism and epilepsy. More than 20 years ago, a first animal model was described, the Fmr1 knock-out mouse. Several other models have been developed since then, including conditional knock-out mice, knock-out rats, a zebrafish and a drosophila model. Using these model systems, various targets for potential pharmaceutical treatments have been identified and many treatments have been shown to be efficient in preclinical studies. However, all attempts to turn these findings into a therapy for patients have failed thus far. In this review, I will discuss underlying difficulties and address potential alternatives for our future research. PMID:29599705

Fragile X Mental Retardation Protein (FMRP) controls diacylglycerol kinase activity in neurons.

PubMed

Tabet, Ricardos; Moutin, Enora; Becker, Jérôme A J; Heintz, Dimitri; Fouillen, Laetitia; Flatter, Eric; Krężel, Wojciech; Alunni, Violaine; Koebel, Pascale; Dembélé, Doulaye; Tassone, Flora; Bardoni, Barbara; Mandel, Jean-Louis; Vitale, Nicolas; Muller, Dominique; Le Merrer, Julie; Moine, Hervé

2016-06-28

Fragile X syndrome (FXS) is caused by the absence of the Fragile X Mental Retardation Protein (FMRP) in neurons. In the mouse, the lack of FMRP is associated with an excessive translation of hundreds of neuronal proteins, notably including postsynaptic proteins. This local protein synthesis deregulation is proposed to underlie the observed defects of glutamatergic synapse maturation and function and to affect preferentially the hundreds of mRNA species that were reported to bind to FMRP. How FMRP impacts synaptic protein translation and which mRNAs are most important for the pathology remain unclear. Here we show by cross-linking immunoprecipitation in cortical neurons that FMRP is mostly associated with one unique mRNA: diacylglycerol kinase kappa (Dgkκ), a master regulator that controls the switch between diacylglycerol and phosphatidic acid signaling pathways. The absence of FMRP in neurons abolishes group 1 metabotropic glutamate receptor-dependent DGK activity combined with a loss of Dgkκ expression. The reduction of Dgkκ in neurons is sufficient to cause dendritic spine abnormalities, synaptic plasticity alterations, and behavior disorders similar to those observed in the FXS mouse model. Overexpression of Dgkκ in neurons is able to rescue the dendritic spine defects of the Fragile X Mental Retardation 1 gene KO neurons. Together, these data suggest that Dgkκ deregulation contributes to FXS pathology and support a model where FMRP, by controlling the translation of Dgkκ, indirectly controls synaptic proteins translation and membrane properties by impacting lipid signaling in dendritic spine.

A mouse model of fragile X syndrome exhibits heightened arousal and/or emotion following errors or reversal of contingencies.

PubMed

Moon, J; Ota, K T; Driscoll, L L; Levitsky, D A; Strupp, B J

2008-07-01

This study was designed to further assess cognitive and affective functioning in a mouse model of Fragile X syndrome (FXS), the Fmr1(tm1Cgr) or Fmr1 "knockout" (KO) mouse. Male KO mice and wild-type littermate controls were tested on learning set and reversal learning tasks. The KO mice were not impaired in associative learning, transfer of learning, or reversal learning, based on measures of learning rate. Analyses of videotapes of the reversal learning task revealed that both groups of mice exhibited higher levels of activity and wall-climbing during the initial sessions of the task than during the final sessions, a pattern also seen for trials following an error relative to those following a correct response. Notably, the increase in both behavioral measures seen early in the task was significantly more pronounced for the KO mice than for controls, as was the error-induced increase in activity level. This pattern of effects suggests that the KO mice reacted more strongly than controls to the reversal of contingencies and pronounced drop in reinforcement rate, and to errors in general. This pattern of effects is consistent with the heightened emotional reactivity frequently described for humans with FXS. (c) 2008 Wiley Periodicals, Inc.

R-Baclofen Reverses a Social Behavior Deficit and Elevated Protein Synthesis in a Mouse Model of Fragile X Syndrome.

PubMed

Qin, Mei; Huang, Tianjian; Kader, Michael; Krych, Leland; Xia, Zengyan; Burlin, Thomas; Zeidler, Zachary; Zhao, Tingrui; Smith, Carolyn B

2015-03-28

Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability and the single genomic cause of autism spectrum disorders. It is caused by the absence of a fragile X mental retardation gene (Fmr1) product, FMRP, an RNA-binding translation suppressor. Elevated rates of protein synthesis in the brain and an imbalance between synaptic signaling via glutamate and γ-aminobutyric acid (GABA) are both considered important in the pathogenesis of FXS. In a mouse model of FXS (Fmr1 knockout [KO]), treatment with R-baclofen reversed some behavioral and biochemical phenotypes. A remaining crucial question is whether R-baclofen is also able to reverse increased brain protein synthesis rates. To answer this question, we measured regional rates of cerebral protein synthesis in vivo with the L-[1-(14)C]leucine method in vehicle- and R-baclofen-treated wildtype and Fmr1 KO mice. We further probed signaling pathways involved in the regulation of protein synthesis. Acute R-baclofen administration corrected elevated protein synthesis and reduced deficits on a test of social behavior in adult Fmr1 KO mice. It also suppressed activity of the mammalian target of rapamycin pathway, particularly in synaptosome-enriched fractions, but it had no effect on extracellular-regulated kinase 1/2 activity. Ninety min after R-baclofen treatment, we observed an increase in metabotropic glutamate receptor 5 expression in the frontal cortex, a finding that may shed light on the tolerance observed in human studies with this drug. Our results suggest that treatment via activation of the GABA (GABA receptor subtype B) system warrants further study in patients with FXS. Published by Oxford University Press on behalf of CINP 2015. This work is written by (a) US Government employee(s) and is in the public domain in the US.

Loss of Sodium-Activated Potassium Channel Slack and FMRP Differentially Affect Social Behavior in Mice.

PubMed

Bausch, Anne E; Ehinger, Rebekka; Straubinger, Julia; Zerfass, Patrick; Nann, Yvette; Lukowski, Robert

2018-05-31

The sodium-activated potassium channel Slack (Slo2.2) is widely expressed in central and peripheral neurons where it is supposed to shape firing properties important for neuronal excitability. Slack activity is enhanced by interaction with the Fragile-X-Mental-Retardation-Protein (FMRP) and loss of FMRP leads to decreased sodium-activated potassium currents in medial nucleus of the trapezoid body neurons of the Fmr1-knockout (KO) mouse representing a mouse model of the human Fragile-X-Syndrome (FXS) and autism. Autism is a frequent comorbidity of FXS, but it is unclear whether Slack is involved in autistic or related conditions of FXS in vivo. By applying a wide range of behavioral tests, we compared social and autism-related behaviors in Slack- and FMRP-deficient mice. In our hands, as expected, FMRP-deficiency causes autism-related behavioral changes in nesting and in a marble-burying test. In contrast, Slack-deficient males exhibited specific abnormalities in sociability in direct and indirect social interaction tests. Hence, we show for the first time that a proper Slack channel function is mandatory for normal social behavior in mice. Nevertheless, as deficits in social behaviors seem to occur independently from each other in FMRP and Slack null mutants, we conclude that Slack is not involved in the autistic phenotype of FMRP KO mice. Copyright © 2018 IBRO. Published by Elsevier Ltd. All rights reserved.

Impaired activity-dependent neural circuit assembly and refinement in autism spectrum disorder genetic models

PubMed Central

Doll, Caleb A.; Broadie, Kendal

2014-01-01

Early-use activity during circuit-specific critical periods refines brain circuitry by the coupled processes of eliminating inappropriate synapses and strengthening maintained synapses. We theorize these activity-dependent (A-D) developmental processes are specifically impaired in autism spectrum disorders (ASDs). ASD genetic models in both mouse and Drosophila have pioneered our insights into normal A-D neural circuit assembly and consolidation, and how these developmental mechanisms go awry in specific genetic conditions. The monogenic fragile X syndrome (FXS), a common cause of heritable ASD and intellectual disability, has been particularly well linked to defects in A-D critical period processes. The fragile X mental retardation protein (FMRP) is positively activity-regulated in expression and function, in turn regulates excitability and activity in a negative feedback loop, and appears to be required for the A-D remodeling of synaptic connectivity during early-use critical periods. The Drosophila FXS model has been shown to functionally conserve the roles of human FMRP in synaptogenesis, and has been centrally important in generating our current mechanistic understanding of the FXS disease state. Recent advances in Drosophila optogenetics, transgenic calcium reporters, highly-targeted transgenic drivers for individually-identified neurons, and a vastly improved connectome of the brain are now being combined to provide unparalleled opportunities to both manipulate and monitor A-D processes during critical period brain development in defined neural circuits. The field is now poised to exploit this new Drosophila transgenic toolbox for the systematic dissection of A-D mechanisms in normal versus ASD brain development, particularly utilizing the well-established Drosophila FXS disease model. PMID:24570656

Open-label add-on treatment trial of minocycline in fragile X syndrome.

PubMed

Paribello, Carlo; Tao, Leeping; Folino, Anthony; Berry-Kravis, Elizabeth; Tranfaglia, Michael; Ethell, Iryna M; Ethell, Douglas W

2010-10-11

Fragile X syndrome (FXS) is a disorder characterized by a variety of disabilities, including cognitive deficits, attention-deficit/hyperactivity disorder, autism, and other socio-emotional problems. It is hypothesized that the absence of the fragile X mental retardation protein (FMRP) leads to higher levels of matrix metallo-proteinase-9 activity (MMP-9) in the brain. Minocycline inhibits MMP-9 activity, and alleviates behavioural and synapse abnormalities in fmr1 knockout mice, an established model for FXS. This open-label add-on pilot trial was conducted to evaluate safety and efficacy of minocycline in treating behavioural abnormalities that occur in humans with FXS. Twenty individuals with FXS, ages 13-32, were randomly assigned to receive 100 mg or 200 mg of minocycline daily. Behavioural evaluations were made prior to treatment (baseline) and again 8 weeks after daily minocycline treatment. The primary outcome measure was the Aberrant Behaviour Checklist-Community Edition (ABC-C) Irritability Subscale, and the secondary outcome measures were the other ABC-C subscales, clinical global improvement scale (CGI), and the visual analog scale for behaviour (VAS). Side effects were assessed using an adverse events checklist, a complete blood count (CBC), hepatic and renal function tests, and antinuclear antibody screen (ANA), done at baseline and at 8 weeks. The ABC-C Irritability Subscale scores showed significant improvement (p < 0.001), as did the VAS (p = 0.003) and the CGI (p < 0.001). The only significant treatment-related side effects were minor diarrhea (n = 3) and seroconversion to a positive ANA (n = 2). Results from this study demonstrate that minocycline provides significant functional benefits to FXS patients and that it is well-tolerated. These findings are consistent with the fmr1 knockout mouse model results, suggesting that minocycline modifies underlying neural defects that account for behavioural abnormalities. A placebo-controlled trial of minocycline in FXS is warranted. ClinicalTrials.gov Open-Label Trial NCT00858689.

Developmental Emergence of Phenotypes in the Auditory Brainstem Nuclei of Fmr1 Knockout Mice

PubMed Central

Rotschafer, Sarah E.

2017-01-01

Abstract Fragile X syndrome (FXS), the most common monogenic cause of autism, is often associated with hypersensitivity to sound. Several studies have shown abnormalities in the auditory brainstem in FXS; however, the emergence of these auditory phenotypes during development has not been described. Here, we investigated the development of phenotypes in FXS model [Fmr1 knockout (KO)] mice in the ventral cochlear nucleus (VCN), medial nucleus of the trapezoid body (MNTB), and lateral superior olive (LSO). We studied features of the brainstem known to be altered in FXS or Fmr1 KO mice, including cell size and expression of markers for excitatory (VGLUT) and inhibitory (VGAT) synapses. We found that cell size was reduced in the nuclei with different time courses. VCN cell size is normal until after hearing onset, while MNTB and LSO show decreases earlier. VGAT expression was elevated relative to VGLUT in the Fmr1 KO mouse MNTB by P6, before hearing onset. Because glial cells influence development and are altered in FXS, we investigated their emergence in the developing Fmr1 KO brainstem. The number of microglia developed normally in all three nuclei in Fmr1 KO mice, but we found elevated numbers of astrocytes in Fmr1 KO in VCN and LSO at P14. The results indicate that some phenotypes are evident before spontaneous or auditory activity, while others emerge later, and suggest that Fmr1 acts at multiple sites and time points in auditory system development. PMID:29291238

Critical period inhibition of NKCC1 rectifies synapse plasticity in the somatosensory cortex and restores adult tactile response maps in fragile X mice.

PubMed

He, Qionger; Arroyo, Erica D; Smukowski, Samuel N; Xu, Jian; Piochon, Claire; Savas, Jeffrey N; Portera-Cailliau, Carlos; Contractor, Anis

2018-04-27

Sensory perturbations in visual, auditory and tactile perception are core problems in fragile X syndrome (FXS). In the Fmr1 knockout mouse model of FXS, the maturation of synapses and circuits during critical period (CP) development in the somatosensory cortex is delayed, but it is unclear how this contributes to altered tactile sensory processing in the mature CNS. Here we demonstrate that inhibiting the juvenile chloride co-transporter NKCC1, which contributes to altered chloride homeostasis in developing cortical neurons of FXS mice, rectifies the chloride imbalance in layer IV somatosensory cortex neurons and corrects the development of thalamocortical excitatory synapses during the CP. Comparison of protein abundances demonstrated that NKCC1 inhibition during early development caused a broad remodeling of the proteome in the barrel cortex. In addition, the abnormally large size of whisker-evoked cortical maps in adult Fmr1 knockout mice was corrected by rectifying the chloride imbalance during the early CP. These data demonstrate that correcting the disrupted driving force through GABA A receptors during the CP in cortical neurons restores their synaptic development, has an unexpectedly large effect on differentially expressed proteins, and produces a long-lasting correction of somatosensory circuit function in FXS mice.

Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen.

PubMed

Henderson, Christina; Wijetunge, Lasani; Kinoshita, Mika Nakamoto; Shumway, Matthew; Hammond, Rebecca S; Postma, Friso R; Brynczka, Christopher; Rush, Roger; Thomas, Alexia; Paylor, Richard; Warren, Stephen T; Vanderklish, Peter W; Kind, Peter C; Carpenter, Randall L; Bear, Mark F; Healy, Aileen M

2012-09-19

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism, results from the transcriptional silencing of FMR1 and loss of the mRNA translational repressor protein fragile X mental retardation protein (FMRP). Patients with FXS exhibit changes in neuronal dendritic spine morphology, a pathology associated with altered synaptic function. Studies in the mouse model of fragile X have shown that loss of FMRP causes excessive synaptic protein synthesis, which results in synaptic dysfunction and altered spine morphology. We tested whether the pharmacologic activation of the γ-aminobutyric acid type B (GABA(B)) receptor could correct or reverse these phenotypes in Fmr1-knockout mice. Basal protein synthesis, which is elevated in the hippocampus of Fmr1-knockout mice, was corrected by the in vitro application of the selective GABA(B) receptor agonist STX209 (arbaclofen, R-baclofen). STX209 also reduced to wild-type values the elevated AMPA receptor internalization in Fmr1-knockout cultured neurons, a known functional consequence of increased protein synthesis. Acute administration of STX209 in vivo, at doses that modify behavior, decreased mRNA translation in the cortex of Fmr1-knockout mice. Finally, the chronic administration of STX209 in juvenile mice corrected the increased spine density in Fmr1-knockout mice without affecting spine density in wild-type mice. Thus, activation of the GABA(B) receptor with STX209 corrected synaptic abnormalities considered central to fragile X pathophysiology, a finding that suggests that STX209 may be a potentially effective therapy to treat the core symptoms of FXS.

Oxytocin and vasopressin systems in genetic syndromes and neurodevelopmental disorders.

PubMed

Francis, S M; Sagar, A; Levin-Decanini, T; Liu, W; Carter, C S; Jacob, S

2014-09-11

Oxytocin (OT) and arginine vasopressin (AVP) are two small, related neuropeptide hormones found in many mammalian species, including humans. Dysregulation of these neuropeptides have been associated with changes in behavior, especially social interactions. We review how the OT and AVP systems have been investigated in Autism Spectrum Disorder (ASD), Prader-Willi Syndrome (PWS), Williams Syndrome (WS) and Fragile X syndrome (FXS). All of these neurodevelopmental disorders (NDD) are marked by social deficits. While PWS, WS and FXS have identified genetic mutations, ASD stems from multiple genes with complex interactions. Animal models of NDD are invaluable for studying the role and relatedness of OT and AVP in the developing brain. We present data from a FXS mouse model affecting the fragile X mental retardation 1 (Fmr1) gene, resulting in decreased OT and AVP staining cells in some brain regions. Reviewing the research about OT and AVP in these NDD suggests that altered OT pathways may be downstream from different etiological factors and perturbations in development. This has implications for ongoing studies of the therapeutic application of OT in NDD. This article is part of a Special Issue entitled Oxytocin and Social Behav. Copyright © 2014. Published by Elsevier B.V.

Matrix metalloproteinase-9 deletion rescues auditory evoked potential habituation deficit in a mouse model of Fragile X Syndrome.

PubMed

Lovelace, Jonathan W; Wen, Teresa H; Reinhard, Sarah; Hsu, Mike S; Sidhu, Harpreet; Ethell, Iryna M; Binder, Devin K; Razak, Khaleel A

2016-05-01

Sensory processing deficits are common in autism spectrum disorders, but the underlying mechanisms are unclear. Fragile X Syndrome (FXS) is a leading genetic cause of intellectual disability and autism. Electrophysiological responses in humans with FXS show reduced habituation with sound repetition and this deficit may underlie auditory hypersensitivity in FXS. Our previous study in Fmr1 knockout (KO) mice revealed an unusually long state of increased sound-driven excitability in auditory cortical neurons suggesting that cortical responses to repeated sounds may exhibit abnormal habituation as in humans with FXS. Here, we tested this prediction by comparing cortical event related potentials (ERP) recorded from wildtype (WT) and Fmr1 KO mice. We report a repetition-rate dependent reduction in habituation of N1 amplitude in Fmr1 KO mice and show that matrix metalloproteinase-9 (MMP-9), one of the known FMRP targets, contributes to the reduced ERP habituation. Our studies demonstrate a significant up-regulation of MMP-9 levels in the auditory cortex of adult Fmr1 KO mice, whereas a genetic deletion of Mmp-9 reverses ERP habituation deficits in Fmr1 KO mice. Although the N1 amplitude of Mmp-9/Fmr1 DKO recordings was larger than WT and KO recordings, the habituation of ERPs in Mmp-9/Fmr1 DKO mice is similar to WT mice implicating MMP-9 as a potential target for reversing sensory processing deficits in FXS. Together these data establish ERP habituation as a translation relevant, physiological pre-clinical marker of auditory processing deficits in FXS and suggest that abnormal MMP-9 regulation is a mechanism underlying auditory hypersensitivity in FXS. Fragile X Syndrome (FXS) is the leading known genetic cause of autism spectrum disorders. Individuals with FXS show symptoms of auditory hypersensitivity. These symptoms may arise due to sustained neural responses to repeated sounds, but the underlying mechanisms remain unclear. For the first time, this study shows deficits in habituation of neural responses to repeated sounds in the Fmr1 KO mice as seen in humans with FXS. We also report an abnormally high level of matrix metalloprotease-9 (MMP-9) in the auditory cortex of Fmr1 KO mice and that deletion of Mmp-9 from Fmr1 KO mice reverses habituation deficits. These data provide a translation relevant electrophysiological biomarker for sensory deficits in FXS and implicate MMP-9 as a target for drug discovery. Copyright © 2016 Elsevier Inc. All rights reserved.

Neural circuit architecture defects in a Drosophila model of Fragile X syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase

PubMed Central

Siller, Saul S.; Broadie, Kendal

2011-01-01

SUMMARY Fragile X syndrome (FXS), caused by loss of the fragile X mental retardation 1 (FMR1) product (FMRP), is the most common cause of inherited intellectual disability and autism spectrum disorders. FXS patients suffer multiple behavioral symptoms, including hyperactivity, disrupted circadian cycles, and learning and memory deficits. Recently, a study in the mouse FXS model showed that the tetracycline derivative minocycline effectively remediates the disease state via a proposed matrix metalloproteinase (MMP) inhibition mechanism. Here, we use the well-characterized Drosophila FXS model to assess the effects of minocycline treatment on multiple neural circuit morphological defects and to investigate the MMP hypothesis. We first treat Drosophila Fmr1 (dfmr1) null animals with minocycline to assay the effects on mutant synaptic architecture in three disparate locations: the neuromuscular junction (NMJ), clock neurons in the circadian activity circuit and Kenyon cells in the mushroom body learning and memory center. We find that minocycline effectively restores normal synaptic structure in all three circuits, promising therapeutic potential for FXS treatment. We next tested the MMP hypothesis by assaying the effects of overexpressing the sole Drosophila tissue inhibitor of MMP (TIMP) in dfmr1 null mutants. We find that TIMP overexpression effectively prevents defects in the NMJ synaptic architecture in dfmr1 mutants. Moreover, co-removal of dfmr1 similarly rescues TIMP overexpression phenotypes, including cellular tracheal defects and lethality. To further test the MMP hypothesis, we generated dfmr1;mmp1 double null mutants. Null mmp1 mutants are 100% lethal and display cellular tracheal defects, but co-removal of dfmr1 allows adult viability and prevents tracheal defects. Conversely, co-removal of mmp1 ameliorates the NMJ synaptic architecture defects in dfmr1 null mutants, despite the lack of detectable difference in MMP1 expression or gelatinase activity between the single dfmr1 mutants and controls. These results support minocycline as a promising potential FXS treatment and suggest that it might act via MMP inhibition. We conclude that FMRP and TIMP pathways interact in a reciprocal, bidirectional manner. PMID:21669931

Cellular Basis for Learning Impairment in Fragile X Syndrome

DTIC Science & Technology

2015-08-01

the leading cause of inherited intellectual disability and results in cognitive impairment, hyperactivity , attention deficits , seizure disorders ...impairment, hyperactivity , attention deficits and seizure disorders . Previous studies using a mouse model for FXS (Fmr1- KO) have described impairments in...neurogenesis in adult fragile X mice, test fragile X mice for learning deficits in hippocampal-independent tasks, and determine how synaptic

Impaired inhibitory control of cortical synchronization in fragile X syndrome.

PubMed

Paluszkiewicz, Scott M; Olmos-Serrano, Jose Luis; Corbin, Joshua G; Huntsman, Molly M

2011-11-01

Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by severe cognitive impairments, sensory hypersensitivity, and comorbidities with autism and epilepsy. Fmr1 knockout (KO) mouse models of FXS exhibit alterations in excitatory and inhibitory neurotransmission, but it is largely unknown how aberrant function of specific neuronal subtypes contributes to these deficits. In this study we show specific inhibitory circuit dysfunction in layer II/III of somatosensory cortex of Fmr1 KO mice. We demonstrate reduced activation of somatostatin-expressing low-threshold-spiking (LTS) interneurons in response to the group I metabotropic glutamate receptor (mGluR) agonist 3,5-dihydroxyphenylglycine (DHPG) in Fmr1 KO mice, resulting in impaired synaptic inhibition. Paired recordings from pyramidal neurons revealed reductions in synchronized synaptic inhibition and coordinated spike synchrony in response to DHPG, indicating a weakened LTS interneuron network in Fmr1 KO mice. Together, these findings reveal a functional defect in a single subtype of cortical interneuron in Fmr1 KO mice. This defect is linked to altered activity of the cortical network in line with the FXS phenotype.

Abnormal presynaptic short-term plasticity and information processing in a mouse model of fragile X syndrome.

PubMed

Deng, Pan-Yue; Sojka, David; Klyachko, Vitaly A

2011-07-27

Fragile X syndrome (FXS) is the most common inherited form of intellectual disability and the leading genetic cause of autism. It is associated with the lack of fragile X mental retardation protein (FMRP), a regulator of protein synthesis in axons and dendrites. Studies on FXS have extensively focused on the postsynaptic changes underlying dysfunctions in long-term plasticity. In contrast, the presynaptic mechanisms of FXS have garnered relatively little attention and are poorly understood. Activity-dependent presynaptic processes give rise to several forms of short-term plasticity (STP), which is believed to control some of essential neural functions, including information processing, working memory, and decision making. The extent of STP defects and their contributions to the pathophysiology of FXS remain essentially unknown, however. Here we report marked presynaptic abnormalities at excitatory hippocampal synapses in Fmr1 knock-out (KO) mice leading to defects in STP and information processing. Loss of FMRP led to enhanced responses to high-frequency stimulation. Fmr1 KO mice also exhibited abnormal synaptic processing of natural stimulus trains, specifically excessive enhancement during the high-frequency spike discharges associated with hippocampal place fields. Analysis of individual STP components revealed strongly increased augmentation and reduced short-term depression attributable to loss of FMRP. These changes were associated with exaggerated calcium influx in presynaptic neurons during high-frequency stimulation, enhanced synaptic vesicle recycling, and enlarged readily-releasable and reserved vesicle pools. These data suggest that loss of FMRP causes abnormal STP and information processing, which may represent a novel mechanism contributing to cognitive impairments in FXS.

Genetic deletion of regulator of G-protein signaling 4 (RGS4) rescues a subset of fragile X related phenotypes in the FMR1 knockout mouse.

PubMed

Pacey, Laura K K; Doss, Lilian; Cifelli, Carlo; van der Kooy, Derek; Heximer, Scott P; Hampson, David R

2011-03-01

Fragile X syndrome (FXS), the most common cause of inherited mental retardation, is caused by the loss of the mRNA binding protein, FMRP. Persons with FXS also display epileptic seizures, social anxiety, hyperactivity, and autistic behaviors. The metabotropic glutamate receptor theory of FXS postulates that in the absence of FMRP, enhanced signaling though G-protein coupled group I metabotropic glutamate receptors in the brain contributes to many of the abnormalities observed in the disorder. However, recent evidence suggests that alterations in cellular signaling through additional G-protein coupled receptors may also be involved in the pathogenesis of FXS, thus providing impetus for examining downstream molecules. One group of signaling molecules situated downstream of the receptors is the regulator of G-protein signaling (RGS) proteins. Notably, RGS4 is highly expressed in brain and has been shown to negatively regulate signaling through Group I mGluRs and GABA(B) receptors. To examine the potential role for RGS4 in the pathogenesis of FXS, we generated FXS/RGS4 double knockout mice. Characterization of these mice revealed that a subset of FXS related phenotypes, including increased body weight, altered synaptic protein expression, and abnormal social behaviors, were rescued in the double knockout mice. Other phenotypes, such as hyperactivity and macroorchidism, were not affected by the loss of RGS4. These findings suggest that tissue and cell-type specific differences in GPCR signaling and RGS function may contribute to the spectrum of phenotypic differences observed in FXS. Copyright © 2010 Elsevier Inc. All rights reserved.

Decreased surface expression of the δ subunit of the GABAA receptor contributes to reduced tonic inhibition in dentate granule cells in a mouse model of fragile X syndrome.

PubMed

Zhang, Nianhui; Peng, Zechun; Tong, Xiaoping; Lindemeyer, A Kerstin; Cetina, Yliana; Huang, Christine S; Olsen, Richard W; Otis, Thomas S; Houser, Carolyn R

2017-11-01

While numerous changes in the GABA system have been identified in models of Fragile X Syndrome (FXS), alterations in subunits of the GABA A receptors (GABA A Rs) that mediate tonic inhibition are particularly intriguing. Considering the key role of tonic inhibition in controlling neuronal excitability, reduced tonic inhibition could contribute to FXS-associated disorders such as hyperactivity, hypersensitivity, and increased seizure susceptibility. The current study has focused on the expression and function of the δ subunit of the GABA A R, a major subunit involved in tonic inhibition, in granule cells of the dentate gyrus in the Fmr1 knockout (KO) mouse model of FXS. Electrophysiological studies of dentate granule cells revealed a marked, nearly four-fold, decrease in tonic inhibition in the Fmr1 KO mice, as well as reduced effects of two δ subunit-preferring pharmacological agents, THIP and DS2, supporting the suggestion that δ subunit-containing GABA A Rs are compromised in the Fmr1 KO mice. Immunohistochemistry demonstrated a small but statistically significant decrease in δ subunit labeling in the molecular layer of the dentate gyrus in Fmr1 KO mice compared to wildtype (WT) littermates. The discrepancy between the large deficits in GABA-mediated tonic inhibition in granule cells in the Fmr1 KO mice and only modest reductions in immunolabeling of the δ subunit led to studies of surface expression of the δ subunit. Cross-linking experiments followed by Western blot analysis demonstrated a small, non-significant decrease in total δ subunit protein in the hippocampus of Fmr1 KO mice, but a four-fold decrease in surface expression of the δ subunit in these mice. No significant changes were observed in total or surface expression of the α4 subunit protein, a major partner of the δ subunit in the forebrain. Postembedding immunogold labeling for the δ subunit demonstrated a large, three-fold, decrease in the number of symmetric synapses with immunolabeling at perisynaptic locations in Fmr1 KO mice. While α4 immunogold particles were also reduced at perisynaptic locations in the Fmr1 KO mice, the labeling was increased at synaptic sites. Together these findings suggest that, in the dentate gyrus, altered surface expression of the δ subunit, rather than a decrease in δ subunit expression alone, could be limiting δ subunit-mediated tonic inhibition in this model of FXS. Finding ways to increase surface expression of the δ subunit of the GABA A R could be a novel approach to treatment of hyperexcitability-related alterations in FXS. Copyright © 2017 Elsevier Inc. All rights reserved.

Environmental Enrichment Reveals Effects of Genotype on Hippocampal Spine Morphologies in the Mouse Model of Fragile X Syndrome

PubMed Central

Lauterborn, Julie C.; Jafari, Matiar; Babayan, Alex H.; Gall, Christine M.

2015-01-01

Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ∼40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS. PMID:24046080

Long-lasting Effects of Minocycline on Behavior in Young but not Adult Fragile X Mice

PubMed Central

Dansie, Lorraine E.; Phommahaxay, Kelly; Okusanya, Ayodeji G.; Uwadia, Jessica; Huang, Mike; Rotschafer, Sarah E.; Razak, Khaleel A.; Ethell, Douglas W.; Ethell, Iryna M.

2013-01-01

Fragile X Syndrome (FXS) is the most common single-gene inherited form of intellectual disability with behaviors characteristic of autism. People with FXS display childhood seizures, hyperactivity, anxiety, developmental delay, attention deficits, and visual-spatial memory impairment, as well as a propensity for obsessive-compulsive disorder (OCD). Several of these aberrant behaviors and FXS-associated synaptic irregularities also occur in “fragile X mental retardation gene” knock-out (Fmr1 KO) mice. We previously reported that minocycline promotes the maturation of dendritic spines - postsynaptic sites for excitatory synapses - in the developing hippocampus of Fmr1 KO mice, which may underlie the beneficial effects of minocycline on anxiolytic behavior in young Fmr1 KO mice. In this study, we compared the effectiveness of minocycline treatment in young and adult Fmr1 KO mice, and determined the dependence of behavioral improvements on short-term versus long-term minocycline administration. We found that 4 and 8 week long treatments significantly reduced locomotor activity in both young and adult Fmr1 KO mice. Some behavioral improvements persisted in young mice post-treatment, but in adults the beneficial effects were lost soon after minocycline treatment was stopped. We also show, for the first time, that minocycline treatment partially attenuates the number and severity of audiogenic seizures in Fmr1 KO mice. This report provides further evidence that minocycline treatment has immediate and long-lasting benefits on FXS-associated behaviors in the Fmr1 KO mouse model. PMID:23660195

Evidence of reactive astrocytes but not peripheral immune system activation in a mouse model of Fragile X Syndrome

PubMed Central

Yuskaitis, Christopher J.; Beurel, Eleonore; Jope, Richard S.

2010-01-01

Fragile X syndrome (FXS) is the most common form of inherited mental retardation and is one of the few known genetic causes of autism. FXS results from the loss of Fmr1 gene function, thus Fmr1 knockout mice provide a model to study impairments associated with FXS and autism and to test potential therapeutic interventions. The inhibitory serine-phosphorylation of glycogen synthase kinase-3 (GSK3) is lower in brain regions of Fmr1 knockout mice than wild-type mice and the GSK3 inhibitor lithium rescues several behavioral impairments in Fmr1 knockout mice. Therefore, we examined if the serine-phosphorylation of GSK3 in Fmr1 knockout mice also was altered outside the brain and if administration of lithium ameliorated the macroorchidism phenotype. Additionally, since GSK3 regulates numerous functions of the immune system and immune alterations have been associated with autism, we tested if immune function is altered in Fmr1 knockout mice. The inhibitory serine-phosphorylation of GSK3 was significantly lower in the testis and liver of Fmr1 knockout mice than wild-type mice, and chronic lithium treatment reduced macroorchidism in Fmr1 knockout mice. No alterations in peripheral immune function were identified in Fmr1 knockout mice. However, examination of glia, the immune cells of the brain, revealed reactive astrocytes in several brain regions of Fmr1 knockout mice and treatment with lithium reduced this in the striatum and cerebellum. These results provide further evidence of the involvement of dysregulated GSK3 in FXS, and demonstrate that lithium administration reduces macroorchidism and reactive astrocytes in Fmr1 knockout mice. PMID:20600866

Fragile x syndrome.

PubMed

McLennan, Yingratana; Polussa, Jonathan; Tassone, Flora; Hagerman, Randi

2011-05-01

Recent data from a national survey highlighted a significant difference in obesity rates in young fragile X males (31%) compared to age matched controls (18%). Fragile X syndrome (FXS) is the most common cause of intellectual disability in males and the most common single gene cause of autism. This X-linked disorder is caused by an expansion of a trinucleotide CGG repeat (>200) on the promotor region of the fragile X mental retardation 1 gene (FMR1). As a result, the promotor region often becomes methylated which leads to a deficiency or absence of the FMR1 protein (FMRP). Common characteristics of FXS include mild to severe cognitive impairments in males but less severe cognitive impairment in females. Physical features of FXS include an elongated face, prominent ears, and post-pubertal macroorchidism. Severe obesity in full mutation males is often associated with the Prader-Willi phenotype (PWP) which includes hyperphagia, lack of satiation after meals, and hypogonadism or delayed puberty; however, there is no deletion at 15q11-q13 nor uniparental maternal disomy. Herein, we discuss the molecular mechanisms leading to FXS and the Prader-Willi phenotype with an emphasis on mouse FMR1 knockout studies that have shown the reversal of weight increase through mGluR antagonists. Finally, we review the current medications used in treatment of FXS including the atypical antipsychotics that can lead to weight gain and the research regarding the use of targeted treatments in FXS that will hopefully have a significantly beneficial effect on cognition and behavior without weight gain.

Chronic pharmacological mGlu5 inhibition corrects fragile X in adult mice.

PubMed

Michalon, Aubin; Sidorov, Michael; Ballard, Theresa M; Ozmen, Laurence; Spooren, Will; Wettstein, Joseph G; Jaeschke, Georg; Bear, Mark F; Lindemann, Lothar

2012-04-12

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. Previous studies have implicated mGlu5 in the pathogenesis of the disease, but a crucial unanswered question is whether pharmacological mGlu5 inhibition is able to reverse an already established FXS phenotype in mammals. Here we have used the novel, potent, and selective mGlu5 inhibitor CTEP to address this issue in the Fmr1 knockout mouse. Acute CTEP treatment corrects elevated hippocampal long-term depression, protein synthesis, and audiogenic seizures. Chronic treatment that inhibits mGlu5 within a receptor occupancy range of 81% ± 4% rescues cognitive deficits, auditory hypersensitivity, aberrant dendritic spine density, overactive ERK and mTOR signaling, and partially corrects macroorchidism. This study shows that a comprehensive phenotype correction in FXS is possible with pharmacological intervention starting in young adulthood, after development of the phenotype. It is of great interest how these findings may translate into ongoing clinical research testing mGlu5 inhibitors in FXS patients. Copyright © 2012 Elsevier Inc. All rights reserved.

Human pluripotent stem cells in modeling human disorders: the case of fragile X syndrome.

PubMed

Vershkov, Dan; Benvenisty, Nissim

2017-01-01

Human pluripotent stem cells (PSCs) generated from affected blastocysts or from patient-derived somatic cells are an emerging platform for disease modeling and drug discovery. Fragile X syndrome (FXS), the leading cause of inherited intellectual disability, was one of the first disorders modeled in both embryonic stem cells and induced PCSs and can serve as an exemplary case for the utilization of human PSCs in the study of human diseases. Over the past decade, FXS-PSCs have been used to address the fundamental questions regarding the pathophysiology of FXS. In this review we summarize the methodologies for generation of FXS-PSCs, discuss their advantages and disadvantages compared with existing modeling systems and describe their utilization in the study of FXS pathogenesis and in the development of targeted treatment.

Environmental enrichment reveals effects of genotype on hippocampal spine morphologies in the mouse model of Fragile X Syndrome.

PubMed

Lauterborn, Julie C; Jafari, Matiar; Babayan, Alex H; Gall, Christine M

2015-02-01

Fragile X Syndrome (FXS) and the Fmr1 knockout (KO) mouse model of this disorder exhibit abnormal dendritic spines in neocortex, but the degree of spine disturbances in hippocampus is not clear. The present studies tested if the mutation influences dendritic branching and spine measures for CA1 pyramidal cells in Fmr1 KO and wild-type (WT) mice provided standard or enriched environment (EE) housing. Automated measures from 3D reconstructions of green fluorescent protein (GFP)-labeled cells showed that spine head volumes were ∼ 40% lower in KOs when compared with WTs in both housing conditions. With standard housing, average spine length was greater in KOs versus WTs but there was no genotype difference in dendritic branching, numbers of spines, or spine length distribution. However, with EE rearing, significant effects of genotype emerged including greater dendritic branching in WTs, greater spine density in KOs, and greater numbers of short thin spines in KOs when compared with WTs. Thus, EE rearing revealed greater effects of the Fmr1 mutation on hippocampal pyramidal cell morphology than was evident with standard housing, suggesting that environmental enrichment allows for fuller appreciation of the impact of the mutation and better representation of abnormalities likely to be present in human FXS. © The Author 2013. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Excessive Astrocyte-Derived Neurotrophin-3 Contributes to the Abnormal Neuronal Dendritic Development in a Mouse Model of Fragile X Syndrome

PubMed Central

Guo, Yan-yan; Liu, Shui-bing; Wu, Yu-mei; Li, Xiao-qiang; Zhao, Ming-gao

2012-01-01

Fragile X syndrome (FXS) is a form of inherited mental retardation in humans that results from expansion of a CGG repeat in the Fmr1 gene. Recent studies suggest a role of astrocytes in neuronal development. However, the mechanisms involved in the regulation process of astrocytes from FXS remain unclear. In this study, we found that astrocytes derived from a Fragile X model, the Fmr1 knockout (KO) mouse which lacks FMRP expression, inhibited the proper elaboration of dendritic processes of neurons in vitro. Furthermore, astrocytic conditioned medium (ACM) from KO astrocytes inhibited proper dendritic growth of both wild-type (WT) and KO neurons. Inducing expression of FMRP by transfection of FMRP vectors in KO astrocytes restored dendritic morphology and levels of synaptic proteins. Further experiments revealed elevated levels of the neurotrophin-3 (NT-3) in KO ACM and the prefrontal cortex of Fmr1 KO mice. However, the levels of nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF), glial cell-derived neurotrophic factor (GDNF), and ciliary neurotrophic factor (CNTF) were normal. FMRP has multiple RNA–binding motifs and is involved in translational regulation. RNA–binding protein immunoprecipitation (RIP) showed the NT-3 mRNA interacted with FMRP in WT astrocytes. Addition of high concentrations of exogenous NT-3 to culture medium reduced the dendrites of neurons and synaptic protein levels, whereas these measures were ameliorated by neutralizing antibody to NT-3 or knockdown of NT-3 expression in KO astrocytes through short hairpin RNAs (shRNAs). Prefrontal cortex microinjection of WT astrocytes or NT-3 shRNA infected KO astrocytes rescued the deficit of trace fear memory in KO mice, concomitantly decreased the NT-3 levels in the prefrontal cortex. This study indicates that excessive NT-3 from astrocytes contributes to the abnormal neuronal dendritic development and that astrocytes could be a potential therapeutic target for FXS. PMID:23300470

Fragile X syndrome: Are signaling lipids the missing culprits?

PubMed

Tabet, Ricardos; Vitale, Nicolas; Moine, Hervé

2016-11-01

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and autism. FXS results from the absence of FMRP, an RNA binding protein associated to ribosomes that influences the translation of specific mRNAs in post-synaptic compartments of neurons. The main molecular consequence of the absence of FMRP is an excessive translation of neuronal protein in several areas of the brain. This local protein synthesis deregulation is proposed to underlie the defect in synaptic plasticity responsible for FXS. Recent findings in neurons of the fragile X mouse model (Fmr1-KO) uncovered another consequence of the lack of FMRP: a deregulation of the diacylglycerol (DAG)/phosphatidic acid (PA) homeostasis. DAG and PA are two interconvertible lipids that influence membrane architecture and that act as essential signaling molecules that activate various downstream effectors, including master regulators of local protein synthesis and actin polymerization. As a consequence, DAG and PA govern a variety of cellular processes, including cell proliferation, vesicle/membrane trafficking and cytoskeletal organization. At the synapse, the level of these lipids is proposed to influence the synaptic activation status. FMRP appears as a master regulator of this neuronal process by controlling the translation of a diacylglycerol kinase enzyme that converts DAG into PA. The deregulated levels of DAG and PA caused by the absence of FMRP could represent a novel therapeutic target for the treatment of FXS. Copyright © 2016 Elsevier B.V. and Société Française de Biochimie et Biologie Moléculaire (SFBBM). All rights reserved.

Deletion of Fmr1 Alters Function and Synaptic Inputs in the Auditory Brainstem

PubMed Central

Rotschafer, Sarah E.; Marshak, Sonya; Cramer, Karina S.

2015-01-01

Fragile X Syndrome (FXS), a neurodevelopmental disorder, is the most prevalent single-gene cause of autism spectrum disorder. Autism has been associated with impaired auditory processing, abnormalities in the auditory brainstem response (ABR), and reduced cell number and size in the auditory brainstem nuclei. FXS is characterized by elevated cortical responses to sound stimuli, with some evidence for aberrant ABRs. Here, we assessed ABRs and auditory brainstem anatomy in Fmr1 -/- mice, an animal model of FXS. We found that Fmr1 -/- mice showed elevated response thresholds to both click and tone stimuli. Amplitudes of ABR responses were reduced in Fmr1 -/- mice for early peaks of the ABR. The growth of the peak I response with sound intensity was less steep in mutants that in wild type mice. In contrast, amplitudes and response growth in peaks IV and V did not differ between these groups. We did not observe differences in peak latencies or in interpeak latencies. Cell size was reduced in Fmr1 -/- mice in the ventral cochlear nucleus (VCN) and in the medial nucleus of the trapezoid body (MNTB). We quantified levels of inhibitory and excitatory synaptic inputs in these nuclei using markers for presynaptic proteins. We measured VGAT and VGLUT immunolabeling in VCN, MNTB, and the lateral superior olive (LSO). VGAT expression in MNTB was significantly greater in the Fmr1 -/- mouse than in wild type mice. Together, these observations demonstrate that FXS affects peripheral and central aspects of hearing and alters the balance of excitation and inhibition in the auditory brainstem. PMID:25679778

Clinical and Molecular Assessment in a Female with Fragile X Syndrome and Tuberous Sclerosis

PubMed Central

Yrigollen, Carolyn M; Pacini, Laura; Nobile, Veronica; Lozano, Reymundo; Hagerman, Randi J.; Bagni, Claudia; Tassone, Flora

2017-01-01

Objective Fragile X syndrome (FXS) and tuberous sclerosis (TSC) are genetic disorders that result in intellectual disability and an increased prevalence of autism spectrum disorders (ASD). While the clinical presentation of each disorder is distinct, the molecular causes are linked to a disruption in the mTORC1 (mammalian Target of Rapamycin Complex 1) and ERK1/2 (Extracellular signal-Regulated Kinase) signaling pathways. Methods We assessed the clinical and molecular characteristics of an individual seen at the UC Davis MIND Institute with a diagnosis of FXS and TSC. Clinical evaluation of physical, behavioral, and cognitive impairments were performed. Additionally, total and phosphorylated proteins along the mTORC1 and ERK1/2 pathways were measured in primary fibroblast cell lines from the proband. Results In this case the phenotypic effects that result in a human with both FXS and TSC are shown to be severe. Changes in mTORC1 and ERK1/2 signaling proteins and global protein synthesis were not found to be noticeably different between four cohorts (typically developing, FMR1 full mutation, FMR1 full mutation and TSC1 loss of function mutation, and TSC1 loss of function mutation); however cohort sizes prevented stringent comparisons. Conclusion It has previously been suggested that disruption of the mTORC1 pathway was reciprocal in TSC and FXS double knock-out mouse models so that the regulation of these pathways were more similar to wild-type mice compared to mice harboring a Fmr1−/y or Tsc2−/+ mutation alone. However, in this first reported case of a human with a diagnosis of both FXS and TSC, substantial clinical impairments, as a result of these two disorders were observed. Differences in the mTORC and ERK1/2 pathways were not clearly established when compared between individuals with either disorder, or both. PMID:28232951

Fragile X-like behaviors and abnormal cortical dendritic spines in cytoplasmic FMR1-interacting protein 2-mutant mice.

PubMed

Han, Kihoon; Chen, Hogmei; Gennarino, Vincenzo A; Richman, Ronald; Lu, Hui-Chen; Zoghbi, Huda Y

2015-04-01

Silencing of fragile X mental retardation 1 (FMR1) gene and loss of fragile X mental retardation protein (FMRP) cause fragile X syndrome (FXS), a genetic disorder characterized by intellectual disability and autistic behaviors. FMRP is an mRNA-binding protein regulating neuronal translation of target mRNAs. Abnormalities in actin-rich dendritic spines are major neuronal features in FXS, but the molecular mechanism and identity of FMRP targets mediating this phenotype remain largely unknown. Cytoplasmic FMR1-interacting protein 2 (Cyfip2) was identified as an interactor of FMRP, and its mRNA is a highly ranked FMRP target in mouse brain. Importantly, Cyfip2 is a component of WAVE regulatory complex, a key regulator of actin cytoskeleton, suggesting that Cyfip2 could be implicated in the dendritic spine phenotype of FXS. Here, we generated and characterized Cyfip2-mutant (Cyfip2(+/-)) mice. We found that Cyfip2(+/-) mice exhibited behavioral phenotypes similar to Fmr1-null (Fmr1(-/y)) mice, an animal model of FXS. Synaptic plasticity and dendritic spines were normal in Cyfip2(+/-) hippocampus. However, dendritic spines were altered in Cyfip2(+/-) cortex, and the dendritic spine phenotype of Fmr1(-/y) cortex was aggravated in Fmr1(-/y); Cyfip2(+/-) double-mutant mice. In addition to the spine changes at basal state, metabotropic glutamate receptor (mGluR)-induced dendritic spine regulation was impaired in both Fmr1(-/y) and Cyfip2(+/-) cortical neurons. Mechanistically, mGluR activation induced mRNA translation-dependent increase of Cyfip2 in wild-type cortical neurons, but not in Fmr1(-/y) or Cyfip2(+/-) neurons. These results suggest that misregulation of Cyfip2 function and its mGluR-induced expression contribute to the neurobehavioral phenotypes of FXS. © The Author 2014. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.

Expressive morphosyntax in boys with Fragile X syndrome with and without autism spectrum disorder

PubMed Central

Estigarribia, Bruno; Roberts, Joanne Erwick; Sideris, John; Price, Johanna

2010-01-01

Background Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability, and the most common single gene disorder associated with autism. Language impairments in this disorder are well documented, but the nature and extent of syntactic impairments are still unclear. Aims To compare the performance of boys with FXS with and without autism spectrum disorder on measures of verb (VM) and noun (NM) morphosyntax with that of typically developing boys of similar non-verbal mental ages. Methods & Procedures Conversational samples were obtained from 33 boys with FXS with autism spectrum disorder (FXS-ASD), 35 boys with FXS and no ASD (FXS-O), and 46 typically developing boys (TD). Production of verbal and nominal morphosyntax was assessed separately in these two subdomains. A hierarchical linear model compared morphosyntactic scores in all groups after adjusting for non-verbal cognition, articulatory skill, and caregiver education. The model also tested interactions between group and morphosyntactic subdomain. Outcomes & Results Boys with FXS in both groups scored lower than the TD boys on both measures. The FXS-O and the FXS-ASD groups did not differ on either composite measure. All covariates were significantly related to morphosyntactic scores. Conclusions & Implications Part of the morphosyntactic impairment in FXS may be attributable to cognitive, environmental, and speech factors. However, it is clear that boys with FXS perform at levels lower than expected from differences in these extra-linguistic factors alone, across both the verb and the noun domains. Clinical interventions should therefore seek to address specific syntactic targets. PMID:21401819

Autism Spectrum Disorder in Fragile X Syndrome: A Longitudinal Evaluation

PubMed Central

Hernandez, R. Nick; Feinberg, Rachel L.; Vaurio, Rebecca; Passanante, Natalie M.; Thompson, Richard E.; Kaufmann, Walter E.

2009-01-01

The present study extends our previous work on characterizing the autistic behavior profile of boys with fragile X syndrome (FXS) who meet Diagnostic and Statistical Manual for Mental Disorders, 4th Edition criteria for autism spectrum disorder (ASD) into a longitudinal evaluation of ASD in FXS (FXS+ASD). Specifically, we aimed to determine the stability of the diagnosis and profile of ASD in FXS over time. Through regression models, we also evaluated which autistic and social behaviors and skills were correlates of diagnosis and autistic behavior severity (i.e., Autism Diagnostic Interview-Revised total scores). Finally, we assessed the evolution of cognitive parameters in FXS+ASD. A population of 56 boys (30–88 months at baseline) with FXS was evaluated using measures of autistic, social, and cognitive behaviors and skills at three yearly evaluations. We found that the diagnosis of ASD in FXS was relatively stable over time. Further emphasizing this stability, we found a set of behaviors and skills, particularly those related to peer relationships and adaptive socialization, that differentiated FXS+ASD from the rest of the FXS cohort (FXS+None) and contributed to autistic severity at all time points. Nevertheless, the general improvement in autistic behavior observed in FXS+ASD coupled with the concurrent worsening in FXS+None resulted in less differentiation between the groups over time. Surprisingly, FXS+ASD IQ scores were stable while FXS+None non-verbal IQ scores declined. Our findings indicate that ASD is a distinctive subphenotype in FXS characterized by deficits in complex social interaction, with similarities to ASD in the general population. PMID:19441123

Genetic removal of p70 S6 kinase 1 corrects molecular, synaptic, and behavioral phenotypes in fragile X syndrome mice.

PubMed

Bhattacharya, Aditi; Kaphzan, Hanoch; Alvarez-Dieppa, Amanda C; Murphy, Jaclyn P; Pierre, Philippe; Klann, Eric

2012-10-18

Fragile X syndrome (FXS) is the leading inherited cause of autism and intellectual disability. Aberrant synaptic translation has been implicated in the etiology of FXS, but most lines of research on therapeutic strategies have targeted protein synthesis indirectly, far upstream of the translation machinery. We sought to perturb p70 ribosomal S6 kinase 1 (S6K1), a key translation initiation and elongation regulator, in FXS model mice. We found that genetic reduction of S6K1 prevented elevated phosphorylation of translational control molecules, exaggerated protein synthesis, enhanced mGluR-dependent long-term depression (LTD), weight gain, and macro-orchidism in FXS model mice. In addition, S6K1 deletion prevented immature dendritic spine morphology and multiple behavioral phenotypes, including social interaction deficits, impaired novel object recognition, and behavioral inflexibility. Our results support the model that dysregulated protein synthesis is the key causal factor in FXS and that restoration of normal translation can stabilize peripheral and neurological function in FXS. Copyright © 2012 Elsevier Inc. All rights reserved.

Delayed in vitro development of Up states but normal network plasticity in Fragile X circuits.

PubMed

Motanis, Helen; Buonomano, Dean

2015-09-01

A broad range of neurophysiological phenotypes have been reported since the generation of the first mouse model of Fragile X syndrome (FXS). However, it remains unclear which phenotypes are causally related to the cognitive deficits associated with FXS. Indeed, because many of these phenotypes are known to be modulated by experience, a confounding factor in the interpretation of many studies is whether some phenotypes are an indirect consequence of abnormal development and experience. To help diminish this confound we first conducted an in vitro developmental study of spontaneous neural dynamics in cortical organotypic cultures. A significant developmental increase in network activity and Up states was observed in both wild-type and Fmr1(-/y) circuits, along with a specific developmental delay in the emergence of Up states in knockout circuits. To determine whether Up state regulation is generally impaired in FXS circuits, we examined Up state plasticity using chronic optogenetic stimulation. Wild-type and Fmr1(-/y) stimulated circuits exhibited a significant decrease in overall spontaneous activity including Up state frequency; however, no significant effect of genotype was observed. These results demonstrate that developmental delays characteristic of FXS are recapitulated during in vitro development, and that Up state abnormalities are probably a direct consequence of the disease, and not an indirect consequence of abnormal experience. However, the fact that Fmr1(-/y) circuits exhibited normal homeostatic modulation of Up states suggests that these plasticity mechanisms are largely intact, and that some of the previously reported plasticity deficits could reflect abnormal experience or the engagement of compensatory mechanisms. © 2015 Federation of European Neuroscience Societies and John Wiley & Sons Ltd.

Astrocytic Contributions to Synaptic and Learning Abnormalities in a Mouse Model of Fragile X Syndrome.

PubMed

Hodges, Jennifer L; Yu, Xinzhu; Gilmore, Anthony; Bennett, Hannah; Tjia, Michelle; Perna, James F; Chen, Chia-Chien; Li, Xiang; Lu, Ju; Zuo, Yi

2017-07-15

Fragile X syndrome (FXS) is the most common type of mental retardation attributable to a single-gene mutation. It is caused by FMR1 gene silencing and the consequent loss of its protein product, fragile X mental retardation protein. Fmr1 global knockout (KO) mice recapitulate many behavioral and synaptic phenotypes associated with FXS. Abundant evidence suggests that astrocytes are important contributors to neurological diseases. This study investigates astrocytic contributions to the progression of synaptic abnormalities and learning impairments associated with FXS. Taking advantage of the Cre-lox system, we generated and characterized mice in which fragile X mental retardation protein is selectively deleted or exclusively expressed in astrocytes. We performed in vivo two-photon imaging to track spine dynamics/morphology along dendrites of neurons in the motor cortex and examined associated behavioral defects. We found that adult astrocyte-specific Fmr1 KO mice displayed increased spine density in the motor cortex and impaired motor-skill learning. The learning defect coincided with a lack of enhanced spine dynamics in the motor cortex that normally occurs in response to motor skill acquisition. Although spine density was normal at 1 month of age in astrocyte-specific Fmr1 KO mice, new spines formed at an elevated rate. Furthermore, fragile X mental retardation protein expression in only astrocytes was insufficient to rescue most spine or behavioral defects. Our work suggests a joint astrocytic-neuronal contribution to FXS pathogenesis and reveals that heightened spine formation during adolescence precedes the overabundance of spines and behavioral defects found in adult Fmr1 KO mice. Copyright © 2016 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

Characterization and reversal of synaptic defects in the amygdala in a mouse model of fragile X syndrome.

PubMed

Suvrathan, Aparna; Hoeffer, Charles A; Wong, Helen; Klann, Eric; Chattarji, Sumantra

2010-06-22

Fragile X syndrome (FXS), a common inherited form of mental impairment and autism, is caused by transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. Earlier studies have identified a role for aberrant synaptic plasticity mediated by the metabotropic glutamate receptors (mGluRs) in FXS. However, many of these observations are derived primarily from studies in the hippocampus. The strong emotional symptoms of FXS, on the other hand, are likely to involve the amygdala. Unfortunately, little is known about how exactly FXS affects synaptic function in the amygdala. Here, using whole-cell recordings in brain slices from adult Fmr1 knockout mice, we find mGluR-dependent long-term potentiation to be impaired at thalamic inputs to principal neurons in the lateral amygdala. Consistent with this long-term potentiation deficit, surface expression of the AMPA receptor subunit, GluR1, is reduced in the lateral amygdala of knockout mice. In addition to these postsynaptic deficits, lower presynaptic release was manifested by a decrease in the frequency of spontaneous miniature excitatory postsynaptic currents (mEPSCs), increased paired-pulse ratio, and slower use-dependent block of NMDA receptor currents. Strikingly, pharmacological inactivation of mGluR5 with 2-methyl-6-phenylethynyl-pyridine (MPEP) fails to rescue either the deficit in long-term potentiation or surface GluR1. However, the same acute MPEP treatment reverses the decrease in mEPSC frequency, a finding of potential therapeutic relevance. Therefore, our results suggest that synaptic defects in the amygdala of knockout mice are still amenable to pharmacological interventions against mGluR5, albeit in a manner not envisioned in the original hippocampal framework.

A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome.

PubMed

Leigh, Mary Jacena S; Nguyen, Danh V; Mu, Yi; Winarni, Tri I; Schneider, Andrea; Chechi, Tasleem; Polussa, Jonathan; Doucet, Paul; Tassone, Flora; Rivera, Susan M; Hessl, David; Hagerman, Randi J

2013-04-01

Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Previous open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, aged 3.5 years to 16 years (n = 55, mean age 9.2 [SD, 3.6] years). Participants were randomized to minocycline or placebo for 3 months and then switched to the other treatment. Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared with placebo (2.49 ± 0.13 and 2.97 ± 0.13, respectively, p = .0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analog Scale (minocycline: 5.26 cm ± 0.46 cm, placebo: 4.05 cm ± 0.46 cm; p = .0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding, and preliminary efficacy analysis results known to investigators. Minocycline treatment for 3 months in children with FXS resulted in greater global improvement than placebo. Treatment for 3 months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline.

A Randomized Double-Blind, Placebo-Controlled Trial of Minocycline in Children and Adolescents with Fragile X Syndrome

PubMed Central

Leigh, Mary Jacena S.; Nguyen, Danh V.; Mu, Yi; Winarni, Tri I.; Schneider, Andrea; Chechi, Tasleem; Polussa, Jonathan; Doucet, Paul; Tassone, Flora; Rivera, Susan M.; Hessl, David; Hagerman, Randi J.

2013-01-01

Objective Minocycline rescued synaptic abnormalities and improved behavior in the fragile X mouse model. Prior open-label human studies demonstrated benefits in individuals with fragile X syndrome (FXS); however, its efficacy in patients with FXS has not been assessed in a controlled trial. Method Randomized, double-blind, placebo-controlled, crossover trial in individuals with FXS, ages 3.5-16 years (n=55, mean age 9.2 (SD 3.6 years)). Participants were randomized to minocycline or placebo for three months, then switched to the other treatment. Results Sixty-nine subjects were screened and 66 were randomized. Fifty-five subjects (83.3%) completed at least the first period and 48 (72.7%) completed the full trial. Intention-to-treat analysis demonstrated significantly greater improvements in one primary outcome, Clinical Global Impression Scale-Improvement after minocycline compared to placebo (2.49 ±0.13, 2.97 ±0.13, respectively, p 0.0173) and greater improvement in ad hoc analysis of anxiety and mood-related behaviors on the Visual Analoge Scale (minocycline 5.26 cm ±0.46 cm, placebo 4.05 cm±0.46cm; p 0.0488). Side effects were not significantly different during the minocycline and placebo treatments. No serious adverse events occurred on minocycline. Results may be potentially biased by study design weaknesses, including unblinding of subjects when they completed the study, drug-related side effects unblinding and preliminary efficacy analysis results known to investigators. Conclusion Minocycline treatment for three months in children with FXS resulted in greater global improvement than placebo. Treatment for three months appears safe; however, longer trials are indicated to further assess benefits, side effects, and factors associated with a clinical response to minocycline. PMID:23572165

Activity-dependent regulation of release probability at excitatory hippocampal synapses: a crucial role of FMRP in neurotransmission

PubMed Central

Wang, Xiao-Sheng; Peng, Chun-Zi; Cai, Wei-Jun; Xia, Jian; Jin, Daozhong; Dai, Yuqiao; Luo, Xue-Gang; Klyachko, Vitaly A.; Deng, Pan-Yue

2014-01-01

Transcriptional silencing of the Fmr1 gene encoding fragile X mental retardation protein (FMRP) causes Fragile X Syndrome (FXS), the most common form of inherited intellectual disability and the leading genetic cause of autism. FMRP has been suggested to play important roles in regulating neurotransmission and short-term synaptic plasticity at excitatory hippocampal and cortical synapses. However, the origins and the mechanisms of these FMRP actions remain incompletely understood, and the role of FMRP in regulating synaptic release probability and presynaptic function remains debated. Here we used variance-mean analysis and peak scaled nonstationary variance analysis to examine changes in both pre- and postsynaptic parameters during repetitive activity at excitatory CA3-CA1 hippocampal synapses in a mouse model of FXS. Our analyses revealed that loss of FMRP did not affect the basal release probability or basal synaptic transmission, but caused an abnormally elevated release probability specifically during repetitive activity. These abnormalities were not accompanied by changes in EPSC kinetics, quantal size or postsynaptic AMPA receptor conductance. Our results thus indicate that FMRP regulates neurotransmission at excitatory hippocampal synapses specifically during repetitive activity via modulation of release probability in a presynaptic manner. Our study suggests that FMRP function in regulating neurotransmitter release is an activity-dependent phenomenon that may contribute to the pathophysiology of FXS. PMID:24646437

Molecular medicine of fragile X syndrome: based on known molecular mechanisms.

PubMed

Luo, Shi-Yu; Wu, Ling-Qian; Duan, Ran-Hui

2016-02-01

Extensive research on fragile X mental retardation gene knockout mice and mutant Drosophila models has largely expanded our knowledge on mechanism-based treatment of fragile X syndrome (FXS). In light of these findings, several clinical trials are now underway for therapeutic translation to humans. Electronic literature searches were conducted using the PubMed database and ClinicalTrials.gov. The search terms included "fragile X syndrome", "FXS and medication", "FXS and therapeutics" and "FXS and treatment". Based on the publications identified in this search, we reviewed the neuroanatomical abnormalities in FXS patients and the potential pathogenic mechanisms to monitor the progress of FXS research, from basic studies to clinical trials. The pathological mechanisms of FXS were categorized on the basis of neuroanatomy, synaptic structure, synaptic transmission and fragile X mental retardation protein (FMRP) loss of function. The neuroanatomical abnormalities in FXS were described to motivate extensive research into the region-specific pathologies in the brain responsible for FXS behavioural manifestations. Mechanism-directed molecular medicines were classified according to their target pathological mechanisms, and the most recent progress in clinical trials was discussed. Current mechanism-based studies and clinical trials have greatly contributed to the development of FXS pharmacological therapeutics. Research examining the extent to which these treatments provided a rescue effect or FMRP compensation for the developmental impairments in FXS patients may help to improve the efficacy of treatments.

Rescue of fragile X syndrome phenotypes in Fmr1 KO mice by a BKCa channel opener molecule

PubMed Central

2014-01-01

Background Fragile X Syndrome (FXS) is the most common form of inherited intellectual disability and is also associated with autism spectrum disorders. Previous studies implicated BKCa channels in the neuropathogenesis of FXS, but the main question was whether pharmacological BKCa stimulation would be able to rescue FXS neurobehavioral phenotypes. Methods and results We used a selective BKCa channel opener molecule (BMS-204352) to address this issue in Fmr1 KO mice, modeling the FXS pathophysiology. In vitro, acute BMS-204352 treatment (10 μM) restored the abnormal dendritic spine phenotype. In vivo, a single injection of BMS-204352 (2 mg/kg) rescued the hippocampal glutamate homeostasis and the behavioral phenotype. Indeed, disturbances in social recognition and interaction, non-social anxiety, and spatial memory were corrected by BMS-204352 in Fmr1 KO mice. Conclusion These results demonstrate that the BKCa channel is a new therapeutic target for FXS. We show that BMS-204352 rescues a broad spectrum of behavioral impairments (social, emotional and cognitive) in an animal model of FXS. This pharmacological molecule might open new ways for FXS therapy. PMID:25079250

Early identification of autism in fragile X syndrome: a review

PubMed Central

McCary, L. M.; Roberts, J. E.

2014-01-01

Fragile X syndrome (FXS) is the leading genetic cause of autism, accounting for approximately 5% of autism cases with as many as 50% of individuals with FXS meeting DSM-IV-TR criteria for autistic disorder. Both FXS and idiopathic autism (IA) are attributed to genetic causes; however, FXS is an identified single gene disorder whereas autism is a complex disorder with multiple potential causes, some of which have been identified. Studies in IA have focused on the prospective longitudinal examination of infant siblings of children with autism as a target group due to their high risk of developing the disorder. We propose that this same model be applied to the study of infants with FXS. There is a lack of research focusing on the early development of autism within FXS and debate in the literature regarding how to best conceptualise this co-morbidity or whether it should be considered a co-morbid condition at all. Studying the emergence and stability of autism in infants with FXS has multiple benefits such as clarifying the underlying mechanisms of the development of autism in FXS and solidifying similarities and differences between co-morbid FXS with autism and IA. Infant research in both IA and FXS are discussed as well as conclusions and implications for practice and future research. PMID:22974167

Effects of a social stimulus on gene expression in a mouse model of fragile X syndrome.

PubMed

Rogers, Tiffany D; Anacker, Allison M J; Kerr, Travis M; Forsberg, C Gunnar; Wang, Jing; Zhang, Bing; Veenstra-VanderWeele, Jeremy

2017-01-01

People with fragile X syndrome (FXS) often have deficits in social behavior, and a substantial portion meet criteria for autism spectrum disorder. Though the genetic cause of FXS is known to be due to the silencing of FMR1 , and the Fmr1 null mouse model representing this lesion has been extensively studied, the contributions of this gene and its protein product, FMRP, to social behavior are not well understood. Fmr1 null mice and wildtype littermates were exposed to a social or non-social stimulus. In one experiment, subjects were assessed for expression of the inducible transcription factor c-Fos in response to the stimulus, to detect brain regions with social-specific activity. In a separate experiment, tissue was taken from those brain regions showing differential activity, and RNA sequencing was performed. Immunohistochemistry revealed a significantly greater number of c-Fos-positive cells in the lateral amygdala and medial amygdala in the brains of mice exposed to a social stimulus, compared to a non-social stimulus. In the prelimbic cortex, there was no significant effect of social stimulus; although the number of c-Fos-positive cells was lower in the social condition compared to the non-social condition, and negatively correlated with c-Fos in the amygdala. RNA sequencing revealed differentially expressed genes enriched for molecules known to interact with FMRP and also for autism-related genes identified in the Simons Foundation Autism Research Initiative gene database. Ingenuity Pathway Analysis detected enrichment of differentially expressed genes in networks and pathways related to neuronal development, intracellular signaling, and inflammatory response. Using the Fmr1 null mouse model of fragile X syndrome, we have identified brain regions, gene networks, and molecular pathways responsive to a social stimulus. These findings, and future experiments following up on the role of specific gene networks, may shed light on the neural mechanisms underlying dysregulated social behaviors in fragile X syndrome and more broadly.

Modelling fragile X syndrome in the laboratory setting: A behavioral perspective.

PubMed

Melancia, Francesca; Trezza, Viviana

2018-04-25

Fragile X syndrome is the most common form of inherited mental retardation and the most frequent monogenic cause of syndromic autism spectrum disorders. The syndrome is caused by the loss of the Fragile X Mental Retardation Protein (FMRP), a key RNA-binding protein involved in synaptic plasticity and neuronal morphology. Patients show intellectual disability, social deficits, repetitive behaviors and impairments in social communication. The aim of this review is to outline the importance of behavioral phenotyping of animal models of FXS from a developmental perspective, by showing how the behavioral characteristics of FXS at the clinical level can be translated into effective, developmentally-specific and clinically meaningful behavioral readouts in the laboratory setting. After introducing the behavioral features, diagnostic criteria and off-label pharmacotherapy of FXS, we outline how FXS-relevant behavioral features can be modelled in laboratory animals in the course of development: we review the progress to date, discuss how behavioral phenotyping in animal models of FXS is essential to identify potential treatments, and discuss caveats and future directions in this research field. Copyright © 2018. Published by Elsevier B.V.

Therapeutic Strategies in Fragile X Syndrome: Dysregulated mGluR Signaling and Beyond

PubMed Central

Gross, Christina; Berry-Kravis, Elizabeth M; Bassell, Gary J

2012-01-01

Fragile X syndrome (FXS) is an inherited neurodevelopmental disease caused by loss of function of the fragile X mental retardation protein (FMRP). In the absence of FMRP, signaling through group 1 metabotropic glutamate receptors is elevated and insensitive to stimulation, which may underlie many of the neurological and neuropsychiatric features of FXS. Treatment of FXS animal models with negative allosteric modulators of these receptors and preliminary clinical trials in human patients support the hypothesis that metabotropic glutamate receptor signaling is a valuable therapeutic target in FXS. However, recent research has also shown that FMRP may regulate diverse aspects of neuronal signaling downstream of several cell surface receptors, suggesting a possible new route to more direct disease-targeted therapies. Here, we summarize promising recent advances in basic research identifying and testing novel therapeutic strategies in FXS models, and evaluate their potential therapeutic benefits. We provide an overview of recent and ongoing clinical trials motivated by some of these findings, and discuss the challenges for both basic science and clinical applications in the continued development of effective disease mechanism-targeted therapies for FXS. PMID:21796106

Human pluripotent stem cell models of Fragile X syndrome.

PubMed

Bhattacharyya, Anita; Zhao, Xinyu

2016-06-01

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and autism. The causal mutation in FXS is a trinucleotide CGG repeat expansion in the FMR1 gene that leads to human specific epigenetic silencing and loss of Fragile X Mental Retardation Protein (FMRP) expression. Human pluripotent stem cells (PSCs), including human embryonic stem cells (ESCs) and particularly induced PSCs (iPSCs), offer a model system to reveal cellular and molecular events underlying human neuronal development and function in FXS. Human FXS PSCs have been established and have provided insight into the epigenetic silencing of the FMR1 gene as well as aspects of neuronal development. Copyright © 2015 Elsevier Inc. All rights reserved.

Dendritic spine instability and insensitivity to modulation by sensory experience in a mouse model of fragile X syndrome.

PubMed

Pan, Feng; Aldridge, Georgina M; Greenough, William T; Gan, Wen-Biao

2010-10-12

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and is caused by transcriptional inactivation of the X-linked fragile X mental retardation 1 (FMR1) gene. FXS is associated with increased density and abnormal morphology of dendritic spines, the postsynaptic sites of the majority of excitatory synapses. To better understand how lack of the FMR1 gene function affects spine development and plasticity, we examined spine formation and elimination of layer 5 pyramidal neurons in the whisker barrel cortex of Fmr1 KO mice with a transcranial two-photon imaging technique. We found that the rates of spine formation and elimination over days to weeks were significantly higher in both young and adult KO mice compared with littermate controls. The heightened spine turnover in KO mice was due to the existence of a larger pool of "short-lived" new spines in KO mice than in controls. Furthermore, we found that the formation of new spines and the elimination of existing ones were less sensitive to modulation by sensory experience in KO mice. These results indicate that the loss of Fmr1 gene function leads to ongoing overproduction of transient spines in the primary somatosensory cortex. The insensitivity of spine formation and elimination to sensory alterations in Fmr1 KO mice suggest that the developing synaptic circuits may not be properly tuned by sensory stimuli in FXS.

Glycogen synthase kinase-3 inhibitors reverse deficits in long-term potentiation and cognition in Fragile X mice

PubMed Central

Franklin, Aimee V.; King, Margaret K.; Palomo, Valle; Martinez, Ana; McMahon, Lori L.; Jope, Richard S.

2013-01-01

Background Identifying feasible therapeutic interventions is crucial for ameliorating the intellectual disability and other afflictions of Fragile X Syndrome (FXS), the most common inherited cause of intellectual disability and autism. Hippocampal glycogen synthase kinase-3 (GSK3) is hyperactive in the mouse model of FXS (FX mice), and hyperactive GSK3 promotes locomotor hyperactivity and audiogenic seizure susceptibility in FX mice, raising the possibility that specific GSK3 inhibitors may improve cognitive processes. Methods We tested if specific GSK3 inhibitors improve deficits in N-methyl-D-aspartate receptor (NMDAR)-dependent long term potentiation (LTP) at medial perforant path synapses onto dentate granule cells (MPP-DGC) and dentate gyrus-dependent cognitive behavioral tasks. Results GSK3 inhibitors completely rescued deficits in LTP at MPP-DGC synapses in FX mice. Furthermore, synaptosomes from the dentate gyrus of FX mice displayed decreased inhibitory serine-phosphorylation of GSK3β compared with wild-type littermates. The potential therapeutic utility of GSK3 inhibitors was further tested on dentate gyrus-dependent congnitive behaviors. In vivo administration of GSK3 inhibitors completely reversed impairments in several cognitive tasks in FX mice, including novel object detection, coordinate and categorical spatial processing, and temporal ordering for visual objects. Conclusions These findings establish that synaptic plasticity and cognitive deficits in FX mice can be improved by intervention with inhibitors of GSK3, which may prove therapeutically beneficial in FXS. PMID:24041505

Chronic minocycline treatment improves social recognition memory in adult male Fmr1 knockout mice.

PubMed

Yau, Suk Yu; Chiu, Christine; Vetrici, Mariana; Christie, Brian R

2016-10-01

Fragile X syndrome (FXS) is caused by a mutation in the Fmr1 gene that leads to silencing of the gene and a loss of its gene product, Fragile X mental retardation protein (FMRP). Some of the key behavioral phenotypes for FXS include abnormal social anxiety and sociability. Here we show that Fmr1 knock-out (KO) mice exhibit impaired social recognition when presented with a novel mouse, and they display normal social interactions in other sociability tests. Administering minocycline to Fmr1 KO mice throughout critical stages of neural development improved social recognition memory in the novel mouse recognition task. To determine if synaptic changes in the prefrontal cortex (PFC) could have played a role in this improvement, we examined PSD-95, a member of the membrane-associated guanylate kinase family, and signaling molecules (ERK1/2, and Akt) linked to synaptic plasticity in the PFC. Our analyses indicated that while minocycline treatment can enhance behavioral performance, it does not enhance expression of PSD-95, ERK1/2 or Akt in the PFC. Copyright © 2016 Elsevier B.V. All rights reserved.

Impaired activity-dependent FMRP translation and enhanced mGluR-dependent LTD in Fragile X premutation mice

PubMed Central

Iliff, Adam J.; Renoux, Abigail J.; Krans, Amy; Usdin, Karen; Sutton, Michael A.; Todd, Peter K.

2013-01-01

Fragile X premutation-associated disorders, including Fragile X-associated Tremor Ataxia Syndrome, result from unmethylated CGG repeat expansions in the 5′ untranslated region (UTR) of the FMR1 gene. Premutation-sized repeats increase FMR1 transcription but impair rapid translation of the Fragile X mental retardation protein (FMRP), which is absent in Fragile X Syndrome (FXS). Normally, FMRP binds to RNA and regulates metabotropic glutamate receptor (mGluR)-mediated synaptic translation, allowing for dendritic synthesis of several proteins. FMRP itself is also synthesized at synapses in response to mGluR activation. However, the role of activity-dependent translation of FMRP in synaptic plasticity and Fragile X-premutation-associated disorders is unknown. To investigate this question, we utilized a CGG knock-in mouse model of the Fragile X premutation with 120–150 CGG repeats in the mouse Fmr1 5′ UTR. These mice exhibit increased Fmr1 mRNA production but impaired FMRP translational efficiency, leading to a modest reduction in basal FMRP expression. Cultured hippocampal neurons and synaptoneurosomes derived from CGG KI mice demonstrate impaired FMRP translation in response to the group I mGluR agonist 3,5-dihydroxyphenylglycine. Electrophysiological analysis reveals enhanced mGluR-mediated long-term depression (mGluR-LTD) at CA3–CA1 synapses in acute hippocampal slices prepared from CGG KI mice relative to wild-type littermates, similar to Fmr1 knockout mice. However, unlike mGluR-LTD in mice completely lacking FMRP, mGluR-LTD in CGG knock-in mice remains dependent on new protein synthesis. These studies demonstrate partially overlapping synaptic plasticity phenotypes in mouse models of FXS and Fragile X premutation disorders and support a role for activity-dependent synthesis of FMRP in enduring forms of synaptic plasticity. PMID:23250915

Lithium treatment alleviates impaired cognition in a mouse model of Fragile X Syndrome

PubMed Central

King, Margaret K.; Jope, Richard S.

2013-01-01

Fragile X Syndrome (FXS) is caused by suppressed expression of fragile X mental retardation protein (FMRP), which results in intellectual disability accompanied by many variably manifested characteristics, such as hyperactivity, seizures, and autistic-like behaviors. Treatment of mice that lack FMRP, Fmr1 knockout (KO) mice, with lithium has been reported to ameliorate locomotor hyperactivity, prevent hypersensitivity to audiogenic seizures, improve passive avoidance behavior, and attenuate sociability deficits. To focus on the defining characteristic of FXS, which is cognitive impairment, we tested if lithium treatment ameliorated impairments in four cognitive tasks in Fmr1 KO mice, tested if the response to lithium differed in adolescent and adult mice, and tested if therapeutic effects persisted after discontinuation of lithium administration. Fmr1 KO mice displayed impaired cognition in the novel object detection task, temporal ordering for objects task, and coordinate and categorical spatial processing tasks. Chronic lithium treatment of adolescent (from 4–8 weeks of age) and adult (from 8–12 weeks of age) mice abolished cognitive impairments in all four cognitive tasks. Cognitive deficits returned after lithium treatment was discontinued for 4 weeks. These results demonstrate that Fmr1 KO mice exhibit severe impairments in these cognitive tasks, that lithium is equally effective in normalizing cognition in these tasks whether it is administered to young or adult mice, and that lithium administration must be continued for the cognitive improvements to be sustained. These findings provide further evidence that lithium administration may be beneficial for individuals with FXS. PMID:23941202

Novel Roles of Amyloid-Beta Protein Precursor Metabolites in Fragile X Syndrome and Autism

PubMed Central

Westmark, Cara J.; Sokol, Deborah K.; Maloney, Bryan; Lahiri, Debomoy K.

2017-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and is associated with up to 5% of autism cases. Several promising drugs are in preclinical testing for FXS; however, bench-to-bedside plans for the clinic are severely limited due to lack of validated biomarkers and outcome measures. Published work from our laboratories has demonstrated altered levels of amyloid-beta (Aβ) protein precursor (APP) and its metabolites in FXS and idiopathic autism. Westmark and colleagues have focused on β-secretase (amyloidogenic) processing and the accumulation of Aβ peptides in adult FXS models while Lahiri and Sokol have studied α-secretase (nonamyloidogenic or anabolic) processing and altered levels of sAPPα and Aβ in pediatric autism and FXS. Thus, our groups have hypothesized a pivotal role for these Alzheimer’s disease (AD)-related proteins in the neurodevelopmental disorders of FXS and autism. In this review, we discuss the contribution of APP metabolites to FXS and autism pathogenesis as well as the potential use of these metabolites as blood-based biomarkers and therapeutic targets. Our future focus is to identify key underlying mechanisms through which APP metabolites contribute to FXS and autism condition-to-disease pathology. Positive outcomes will support utilizing APP metabolites as blood-based biomarkers in clinical trials as well as testing drugs that modulate APP processing as potential disease therapeutics. Our studies to understand the role of APP metabolites in developmental conditions such as FXS and autism are a quantum leap for the neuroscience field, which has traditionally restricted any role of APP to AD and aging. PMID:27573877

Early Negative Affect Predicts Anxiety, not Autism, in Preschool Boys with Fragile X Syndrome

PubMed Central

Tonnsen, Bridgette L.; Malone, Patrick S.; Hatton, Deborah D.

2012-01-01

Children with fragile X syndrome (FXS) face high risk for anxiety disorders, yet no studies have explored FXS as a high-risk sample for investigating early manifestations of anxiety outcomes. Negative affect is one of the most salient predictors of problem behaviors and has been associated with both anxiety and autistic outcomes in clinical and non-clinical pediatric samples. In light of the high comorbidity between autism and anxiety within FXS, the present study investigates the relationship between longitudinal trajectories of negative affect (between 8 and 71 months) and severity of anxiety and autistic outcomes in young males with FXS (n= 25). Multilevel models indicated associations between elevated anxiety and higher fear and sadness, lower soothability, and steeper longitudinal increases in approach. Autistic outcomes were unrelated to negative affect. These findings suggest early negative affect differentially predicts anxiety, not autistic symptoms, within FXS. Future research is warranted to determine the specificity of the relationship between negative affect and anxiety, as well as to explore potential moderators. Characterizing the relationship between early negative affect and anxiety within FXS may inform etiology and treatment considerations specific to children with FXS, as well as lend insight into precursors of anxiety disorders in other clinical groups and community samples. PMID:23011214

Dysregulated nitric oxide signaling as a candidate mechanism of fragile X syndrome and other neuropsychiatric disorders.

PubMed

Colvin, Steven M; Kwan, Kenneth Y

2014-01-01

A mechanistic understanding of the pathophysiology underpinning psychiatric disorders is essential for the development of targeted molecular therapies. For fragile X syndrome (FXS), recent mechanistic studies have been focused on the metabotropic glutamate receptor (mGluR) signaling pathway. This line of research has led to the discovery of promising candidate drugs currently undergoing various phases of clinical trial, and represents a model of how biological insights can inform therapeutic strategies in neurodevelopmental disorders. Although mGluR signaling is a key mechanism at which targeted treatments can be directed, it is likely to be one of many mechanisms contributing to FXS. A more complete understanding of the molecular and neural underpinnings of the disorder is expected to inform additional therapeutic strategies. Alterations in the assembly of neural circuits in the neocortex have been recently implicated in genetic studies of autism and schizophrenia, and may also contribute to FXS. In this review, we explore dysregulated nitric oxide signaling in the developing neocortex as a novel candidate mechanism of FXS. This possibility stems from our previous work demonstrating that neuronal nitric oxide synthase 1 (NOS1 or nNOS) is regulated by the FXS protein FMRP in the mid-fetal human neocortex. Remarkably, in the mid-late fetal and early postnatal neocortex of human FXS patients, NOS1 expression is severely diminished. Given the role of nitric oxide in diverse neural processes, including synaptic development and plasticity, the loss of NOS1 in FXS may contribute to the etiology of the disorder. Here, we outline the genetic and neurobiological data that implicate neocortical dysfunction in FXS, review the evidence supporting dysregulated nitric oxide signaling in the developing FXS neocortex and its contribution to the disorder, and discuss the implications for targeting nitric oxide signaling in the treatment of FXS and other psychiatric illnesses.

Reducing eIF4E-eIF4G interactions restores the balance between protein synthesis and actin dynamics in fragile X syndrome model mice.

PubMed

Santini, Emanuela; Huynh, Thu N; Longo, Francesco; Koo, So Yeon; Mojica, Edward; D'Andrea, Laura; Bagni, Claudia; Klann, Eric

2017-11-07

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which subsequently sequesters and inhibits eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP-eIF4E complex and the Rac1-Wave regulatory complex, thereby connecting translational regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP. Treating FXS mice with 4EGI-1, which blocks interactions between eIF4E and eIF4G, a critical interaction partner for translational initiation, reversed defects in hippocampus-dependent memory and spine morphology. We also found that 4EGI-1 normalized the phenotypes of enhanced metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), enhanced Rac1-p21-activated kinase (PAK)-cofilin signaling, altered actin dynamics, and dysregulated CYFIP1/eIF4E and CYFIP1/Rac1 interactions in FXS mice. Our findings are consistent with the idea that an imbalance in protein synthesis and actin dynamics contributes to pathophysiology in FXS mice, and suggest that targeting eIF4E may be a strategy for treating FXS. Copyright © 2017 The Authors, some rights reserved; exclusive licensee American Association for the Advancement of Science. No claim to original U.S. Government Works.

Reducing eIF4E-eIF4G Interactions Restores the Balance Between Protein Synthesis and Actin Dynamics in Fragile X Syndrome Model Mice*

PubMed Central

Santini, Emanuela; Huynh, Thu N.; Longo, Francesco; Koo, So Yeon; Mojica, Edward; D’Andrea, Laura; Bagni, Claudia; Klann, Eric

2018-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and autism spectrum disorder. FXS is caused by silencing of the FMR1 gene, which encodes fragile X mental retardation protein (FMRP), an mRNA-binding protein that represses the translation of its target mRNAs. One mechanism by which FMRP represses translation is through its association with cytoplasmic FMRP-interacting protein 1 (CYFIP1), which binds to and sequesters eukaryotic initiation factor 4E (eIF4E). CYFIP1 shuttles between the FMRP–eIF4E complex and the Rac1–Wave regulatory complex, thereby connecting translation regulation to actin dynamics and dendritic spine morphology, which are dysregulated in FXS model mice that lack FMRP. Treating FXS mice with 4EGI-1, which blocks interactions between eIF4E and eukaryotic factor 4G (eIF4G), a critical interacting partner for protein synthesis, reversed defects in hippocampus-dependent memory and spine morphology. We also found that 4EGI-1 normalized the phenotypes of enhanced metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD), upregulated Rac1–p21-activated kinase (PAK)–cofilin signaling, altered actin dynamics, and dysregulated CYFIP1/eIF4E and CYFIP1/Rac1 interactions in FXS mice. Our findings are consistent with the idea that an imbalance of protein synthesis and actin dynamics contributes to pathophysiology in FXS mice, and suggest that targeting eIF4E may be a strategy for treating FXS. PMID:29114037

HPA Axis Function Alters Development of Working Memory in Boys with FXS

PubMed Central

Scherr, Jessica F.; Hahn, Laura J.; Hooper, Stephen R.; Hatton, Deborah; Roberts, Jane E.

2016-01-01

The present study examines verbal working memory over time in boys with fragile X syndrome (FXS) compared to nonverbal mental-age (NVMA) matched, typically developing (TD) boys. Concomitantly, the relationship between cortisol—a physiological marker for stress—and verbal working memory performance over time is examined to understand the role of physiological mechanisms in cognitive development in FXS. Participants were assessed between one and three times over a 2-year time frame using two verbal working memory tests that differ in complexity: memory for words and auditory working memory with salivary cortisol collected at the beginning and end of each assessment. Multilevel modeling results indicate specific deficits over time on the memory for words task in boys with FXS compared to TD controls that is exacerbated by elevated baseline cortisol. Similar increasing rates of growth over time were observed for boys with FXS and TD controls on the more complex auditory working memory task, but only boys with FXS displayed an association of increased baseline cortisol and lower performance. This study highlights the benefit of investigations of how dynamic biological and cognitive factors interact and influence cognitive development over time. PMID:26760450

Increased Training Intensity Induces Proper Membrane Localization of Actin Remodeling Proteins in the Hippocampus Preventing Cognitive Deficits: Implications for Fragile X Syndrome.

PubMed

Martinez, L A; Tejada-Simon, Maria Victoria

2018-06-01

Behavioral intervention therapy has proven beneficial in the treatment of autism and intellectual disabilities (ID), raising the possibility of certain changes in molecular mechanisms activated by these interventions that may promote learning. Fragile X syndrome (FXS) is a neurodevelopmental disorder characterized by autistic features and intellectual disability and can serve as a model to examine mechanisms that promote learning. FXS results from mutations in the fragile X mental retardation 1 gene (Fmr1) that prevents expression of the Fmr1 protein (FMRP), a messenger RNA (mRNA) translation regulator at synapses. Among many other functions, FMRP organizes a complex with the actin cytoskeleton-regulating small Rho GTPase Rac1. As in humans, Fmr1 KO mice lacking FMRP display autistic-like behaviors and deformities of actin-rich synaptic structures in addition to impaired hippocampal learning and synaptic plasticity. These features have been previously linked to proper function of actin remodeling proteins that includes Rac1. An important step in Rac1 activation and function is its translocation to the membrane, where it can influence synaptic actin cytoskeleton remodeling during hippocampus-dependent learning. Herein, we report that Fmr1 KO mouse hippocampus exhibits increased levels of membrane-bound Rac1, which may prevent proper learning-induced synaptic changes. We also determine that increasing training intensity during fear conditioning (FC) training restores contextual memory in Fmr1 KO mice and reduces membrane-bound Rac1 in Fmr1 KO hippocampus. Increased training intensity also results in normalized long-term potentiation in hippocampal slices taken from Fmr1 KO mice. These results point to interventional treatments providing new therapeutic options for FXS-related cognitive dysfunction.

Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome

PubMed Central

Ifrim, Marius F.; Williams, Kathryn R.

2015-01-01

Fragile X syndrome (FXS) is caused by the loss of the fragile X mental retardation protein (FMRP), an RNA binding protein that regulates translation of numerous target mRNAs, some of which are dendritically localized. Our previous biochemical studies using synaptoneurosomes demonstrate a role for FMRP and miR-125a in regulating the translation of PSD-95 mRNA. However, the local translation of PSD-95 mRNA within dendrites and spines, as well as the roles of FMRP or miR-125a, have not been directly studied. Herein, local synthesis of a Venus-PSD-95 fusion protein was directly visualized in dendrites and spines using single-molecule imaging of a diffusion-restricted Venus-PSD-95 reporter under control of the PSD-95 3′UTR. The basal translation rates of Venus-PSD-95 mRNA was increased in cultured hippocampal neurons from Fmr1 KO mice compared with WT neurons, which correlated with a transient elevation of endogenous PSD-95 within dendrites. Following mGluR stimulation with (S)-3,5-dihydroxyphenylglycine, the rate of Venus-PSD-95 mRNA translation increased rapidly in dendrites of WT hippocampal neurons, but not in those of Fmr1 KO neurons or when the binding site of miR125a, previously shown to bind PSD-95 3′UTR, was mutated. This study provides direct support for the hypothesis that local translation within dendrites and spines is dysregulated in FXS. Impairments in the regulated local synthesis of PSD-95, a critical regulator of synaptic structure and function, may affect the spatiotemporal control of PSD-95 levels and affect dendritic spine development and synaptic plasticity in FXS. PMID:25948262

Single-Molecule Imaging of PSD-95 mRNA Translation in Dendrites and Its Dysregulation in a Mouse Model of Fragile X Syndrome.

PubMed

Ifrim, Marius F; Williams, Kathryn R; Bassell, Gary J

2015-05-06

Fragile X syndrome (FXS) is caused by the loss of the fragile X mental retardation protein (FMRP), an RNA binding protein that regulates translation of numerous target mRNAs, some of which are dendritically localized. Our previous biochemical studies using synaptoneurosomes demonstrate a role for FMRP and miR-125a in regulating the translation of PSD-95 mRNA. However, the local translation of PSD-95 mRNA within dendrites and spines, as well as the roles of FMRP or miR-125a, have not been directly studied. Herein, local synthesis of a Venus-PSD-95 fusion protein was directly visualized in dendrites and spines using single-molecule imaging of a diffusion-restricted Venus-PSD-95 reporter under control of the PSD-95 3'UTR. The basal translation rates of Venus-PSD-95 mRNA was increased in cultured hippocampal neurons from Fmr1 KO mice compared with WT neurons, which correlated with a transient elevation of endogenous PSD-95 within dendrites. Following mGluR stimulation with (S)-3,5-dihydroxyphenylglycine, the rate of Venus-PSD-95 mRNA translation increased rapidly in dendrites of WT hippocampal neurons, but not in those of Fmr1 KO neurons or when the binding site of miR125a, previously shown to bind PSD-95 3'UTR, was mutated. This study provides direct support for the hypothesis that local translation within dendrites and spines is dysregulated in FXS. Impairments in the regulated local synthesis of PSD-95, a critical regulator of synaptic structure and function, may affect the spatiotemporal control of PSD-95 levels and affect dendritic spine development and synaptic plasticity in FXS. Copyright © 2015 the authors 0270-6474/15/357116-15$15.00/0.

Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice.

PubMed

Sawicka, Kirsty; Pyronneau, Alexander; Chao, Miranda; Bennett, Michael V L; Zukin, R Suzanne

2016-10-11

Fragile X syndrome (FXS) is the most common heritable cause of intellectual disability and a leading genetic form of autism. The Fmr1 KO mouse, a model of FXS, exhibits elevated translation in the hippocampus and the cortex. ERK (extracellular signal-regulated kinase) and mTOR (mechanistic target of rapamycin) signaling regulate protein synthesis by activating downstream targets critical to translation initiation and elongation and are known to contribute to hippocampal defects in fragile X. Here we show that the effect of loss of fragile X mental retardation protein (FMRP) on these pathways is brain region specific. In contrast to the hippocampus, ERK (but not mTOR) signaling is elevated in the neocortex of fragile X mice. Phosphorylation of ribosomal protein S6, typically a downstream target of mTOR, is elevated in the neocortex, despite normal mTOR activity. This is significant in that S6 phosphorylation facilitates translation, correlates with neuronal activation, and is altered in neurodevelopmental disorders. We show that in fragile X mice, S6 is regulated by ERK via the "alternative" S6 kinase p90-ribosomal S6 kinase (RSK), as evidenced by the site of elevated phosphorylation and the finding that ERK inhibition corrects elevated RSK and S6 activity. These findings indicate that signaling networks are altered in the neocortex of fragile X mice such that S6 phosphorylation receives aberrant input from ERK/RSK. Importantly, an RSK inhibitor reduces susceptibility to audiogenic seizures in fragile X mice. Our findings identify RSK as a therapeutic target for fragile X and suggest the therapeutic potential of drugs for the treatment of FXS may vary in a brain-region-specific manner.

Genetic manipulation of STEP reverses behavioral abnormalities in a fragile X syndrome mouse model.

PubMed

Goebel-Goody, S M; Wilson-Wallis, E D; Royston, S; Tagliatela, S M; Naegele, J R; Lombroso, P J

2012-07-01

Fragile X syndrome (FXS), the most common inherited form of intellectual disability and prevailing known genetic basis of autism, is caused by an expansion in the Fmr1 gene that prevents transcription and translation of fragile X mental retardation protein (FMRP). FMRP binds to and controls translation of mRNAs downstream of metabotropic glutamate receptor (mGluR) activation. Recent work shows that FMRP interacts with the transcript encoding striatal-enriched protein tyrosine phosphatase (STEP; Ptpn5). STEP opposes synaptic strengthening and promotes synaptic weakening by dephosphorylating its substrates, including ERK1/2, p38, Fyn and Pyk2, and subunits of N-methyl-d-aspartate (NMDA) and AMPA receptors. Here, we show that basal levels of STEP are elevated and mGluR-dependent STEP synthesis is absent in Fmr1(KO) mice. We hypothesized that the weakened synaptic strength and behavioral abnormalities reported in FXS may be linked to excess levels of STEP. To test this hypothesis, we reduced or eliminated STEP genetically in Fmr1(KO) mice and assessed mice in a battery of behavioral tests. In addition to attenuating audiogenic seizures and seizure-induced c-Fos activation in the periaqueductal gray, genetically reducing STEP in Fmr1(KO) mice reversed characteristic social abnormalities, including approach, investigation and anxiety. Loss of STEP also corrected select nonsocial anxiety-related behaviors in Fmr1(KO) mice, such as light-side exploration in the light/dark box. Our findings indicate that genetically reducing STEP significantly diminishes seizures and restores select social and nonsocial anxiety-related behaviors in Fmr1(KO) mice, suggesting that strategies to inhibit STEP activity may be effective for treating patients with FXS. © 2012 The Authors. Genes, Brain and Behavior © 2012 Blackwell Publishing Ltd and International Behavioural and Neural Genetics Society.

Secondary medical diagnosis in fragile X syndrome with and without autism spectrum disorder.

PubMed

García-Nonell, Catalina; Ratera, Eugenia Rigau; Harris, Susan; Hessl, David; Ono, Michele Y; Tartaglia, Nicole; Marvin, Emily; Tassone, Flora; Hagerman, Randi J

2008-08-01

This study examined whether secondary medical diagnoses that affect CNS function (i.e., seizures, malformations, or genetic disorders), are more likely to occur in individuals with fragile X syndrome (FXS) and autism spectrum disorder (FXS + ASD) or FXS alone. Ninety males (3-25 years) with FXS or FXS + ASD were evaluated for secondary medical diagnoses by medical history and examination. A significant difference in the incidence of medical problems was found between patients with FXS + ASD (38.6%) and FXS alone (18.2%, P < 0.05). Medical problems that affect the CNS are more likely to occur in those with FXS + ASD and it is probable that additional brain dysfunction associated with these medical problems enhance the risk of autism in those with FXS. Copyright 2008 Wiley-Liss, Inc.

Acamprosate rescues neuronal defects in the Drosophila model of Fragile X Syndrome.

PubMed

Hutson, Russell L; Thompson, Rachel L; Bantel, Andrew P; Tessier, Charles R

2018-02-15

Several off-label studies have shown that acamprosate can provide some clinical benefits in youth with Fragile X Syndrome (FXS), an autism spectrum disorder caused by loss of function of the highly conserved FMR1 gene. This study investigated the ability of acamprosate to rescue cellular, molecular and behavioral defects in the Drosophila model of FXS. A high (100μM) and low (10μM) dose of acamprosate was fed to Drosophila FXS (dfmr1 null) or genetic control (w 1118 ) larvae and then analyzed in multiple paradigms. A larval crawling assay was used to monitor aberrant FXS behavior, overgrowth of the neuromuscular junction (NMJ) was quantified to assess neuronal development, and quantitative RT-PCR was used to evaluate expression of deregulated cbp53E mRNA. Acamprosate treatment partially or completely rescued all of the FXS phenotypes analyzed, according to dose. High doses rescued cellular overgrowth and dysregulated cbp53E mRNA expression, but aberrant crawling behavior was not affected. Low doses of acamprosate, however, did not affect synapse number at the NMJ, but could rescue NMJ overgrowth, locomotor defects, and cbp53E mRNA expression. This dual nature of acamprosate suggests multiple molecular mechanisms may be involved in acamprosate function depending on the dosage used. Acamprosate may be a useful therapy for FXS and potentially other autism spectrum disorders. However, understanding the molecular mechanisms involved with different doses of this drug will likely be necessary to obtain optimal results. Copyright © 2018 Elsevier Inc. All rights reserved.

Longitudinal Profiles of Expressive Vocabulary, Syntax, and Pragmatic Language in Boys with Fragile X Syndrome or Down Syndrome

PubMed Central

Martin, Gary E.; Losh, Molly; Estigarribia, Bruno; Sideris, John; Roberts, Joanne

2014-01-01

Background Fragile X syndrome (FXS) and Down syndrome (DS) are the two leading genetic causes of intellectual disability, and FXS is the most common known genetic condition associated with autism. Both FXS and DS are associated with significant language impairment, but little is known about expressive language across domains over time or the role of autism in language development in FXS. Aims To compare three domains of language production (vocabulary, syntax, and pragmatics) over time within and across groups of boys with FXS with and without autism spectrum disorder (FXS-ASD, FXS-O), boys with DS, and typically developing (TD) boys. Methods & Procedures Twenty-nine boys with FXS-O, 40 boys with FXS-ASD, 34 boys with DS, and 48 younger TD boys of similar nonverbal mental age living in the United States participated. The Antonyms, Syntax Construction, and Pragmatic Judgment subtests of the Comprehensive Assessment of Spoken Language were administered annually over three years. Outcomes & Results TD boys scored higher than all other groups on all three subtests, boys with FXS-O and FXS-ASD scored higher than boys with DS in Syntax Construction, and boys with FXS-O scored higher than boys with FXS-ASD in Pragmatic Judgment. Within-group patterns varied between groups. Overall the TD group showed significantly more change over time than all other groups. Conclusions & Implications Findings suggest that expressive language skills and growth across various domains are more impaired in boys with FXS and DS than would be expected based on nonverbal mental age, that for boys with DS syntax is more impaired than would be expected based on intellectual disability, and that autism status affects pragmatic language in boys with FXS. Findings suggest that language production across domains should be addressed during assessment and intervention for boys with FXS and boys with DS, with differing group profiles also suggesting potentially different areas of focus. PMID:23889838

Longitudinal changes in intellectual development in children with Fragile X syndrome.

PubMed

Hall, Scott S; Burns, David D; Lightbody, Amy A; Reiss, Allan L

2008-08-01

Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80 pairs of children received a second evaluation at time 2 approximately 4 years later. Compared to their unaffected siblings, children with FXS obtained significantly lower percentage correct scores on all subtests of the WISC at both time points. During the time between the first and second assessments, the annual rate of intellectual development was approximately 2.2 times faster in the unaffected children compared to the children with FXS. Levels of the fragile X mental retardation protein (FMRP) were highly associated with intellectual ability scores of the children with FXS at both time points (r=0.55 and 0.64 respectively). However, when gender, age, and the time between assessments were included as covariates in the structural equation model, FMRP accounted for only 5% of the variance in intellectual ability scores at time 1 and 13% of the variance at time 2. The results of this study suggest that slower learning contributes to the low and declining standardized IQ scores observed in children with FXS.

Brief Report: Sensorimotor Gating in Idiopathic Autism and Autism Associated with Fragile X Syndrome

ERIC Educational Resources Information Center

Yuhas, Jennifer; Cordeiro, Lisa; Tassone, Flora; Ballinger, Elizabeth; Schneider, Andrea; Long, James M.; Ornitz, Edward M.; Hessl, David

2011-01-01

Prepulse inhibition (PPI) may useful for exploring the proposed shared neurobiology between idiopathic autism and autism caused by FXS. We compared PPI in four groups: typically developing controls (n = 18), FXS and autism (FXS+A; n = 15), FXS without autism spectrum disorder (FXS-A; n = 17), and idiopathic autism (IA; n = 15). Relative to…

The Search for an Effective Therapy to Treat Fragile X Syndrome: Dream or Reality?

PubMed

Castagnola, Sara; Bardoni, Barbara; Maurin, Thomas

2017-01-01

Fragile X Syndrome (FXS) is the most common form of intellectual disability and a primary cause of autism. It originates from the lack of the Fragile X Mental Retardation Protein (FMRP), which is an RNA-binding protein encoded by the Fragile X Mental Retardation Gene 1 ( FMR1 ) gene. Multiple roles have been attributed to this protein, ranging from RNA transport (from the nucleus to the cytoplasm, but also along neurites) to translational control of mRNAs. Over the last 20 years many studies have found a large number of FMRP mRNA targets, but it is still not clear which are those playing a critical role in the etiology of FXS. So far, no therapy for FXS has been found, making the quest for novel targets of considerable importance. Several pharmacological approaches have been attempted, but, despite some promising preclinical results, no strategy gave successful outcomes, due either to the induction of major side effects or to the lack of improvement of the phenotypes. However, these studies suggested that, in order to measure the effectiveness of a specific treatment, trials should be redesigned and new endpoints defined in FXS patients. Nevertheless, the search for new therapeutic targets for FXS is very active. In this context, the advances in animal modeling, coupled with better understanding of neurobiology and physiopathology of FXS, are of crucial importance in developing new selected treatments. Here, we discuss the pathways that were recently linked to the physiopathology of FXS (mGluR, GABAR, insulin, Insulin-like Growth Factor 1 (IGF-1), MPP-9, serotonin, oxytocin and endocannabinoid signaling) and that suggest new approaches to find an effective therapy for this disorder. Our goal with this review article is to summarize some recent relevant findings on FXS treatment strategies in order to have a clearer view of the different pathways analyzed to date emphasizing those shared with other synaptic disorders.

Autism and the synapse: emerging mechanisms and mechanism-based therapies.

PubMed

Ebrahimi-Fakhari, Darius; Sahin, Mustafa

2015-04-01

Recent studies have implicated hundreds of genetic variants in the cause of autism spectrum disorder (ASD). Genes involved in 'monogenic' forms of syndromic ASD converge on common pathways that are involved in synaptic development, plasticity and signaling. In this review, we discuss how these 'developmental synaptopathies' inform our understanding of the molecular disease in ASD and highlight promising approaches that have bridged the gap between the bench and the clinic. Accumulating evidence suggests that synaptic deficits in syndromic and nonsyndromic ASD can be mapped to gene mutations in pathways that control synaptic protein synthesis and degradation, postsynaptic scaffold architecture and neurotransmitter receptors. This is recapitulated in models of Fragile X syndrome (FXS), Tuberous Sclerosis Complex (TSC), Angelman syndrome and Phelan-McDermid syndrome (PMS), all of which cause syndromic ASD. Important recent advances include the development of mouse models and patient-derived induced pluripotent stem cell (iPSC) lines that enable a detailed investigation of synaptic deficits and the identification of potential targets for therapy. Examples of the latter include mGluR5 antagonists in FXS, mTOR inhibitors in TSC and insulin-like growth factor 1 (IGF-1) in PMS. Identifying converging pathways in syndromic forms of ASD will uncover novel therapeutic targets for non-syndromic ASD. Insights into developmental synaptopathies will lead to rational development of mechanism-based therapies and clinical trials that may provide a blueprint for other common pathways implicated in the molecular neuropathology of ASD.

Visual attention and autistic behavior in infants with fragile X syndrome

PubMed Central

Roberts, Jane E.; Hatton, Deborah D.; Bailey, Donald; Long, Anna C. J.; Anello, Vittoria; Colombo, John

2013-01-01

Fragile X syndrome (FXS) is the leading known inherited cause of intellectual disability and the most common known biological cause of autism. Approximately 25% to 50% of males with FXS meet full diagnostic criteria for autism. Despite the high comorbidity between FXS and autism and the ability to diagnose FXS prenatally or at birth, no studies have examined indicators of autism in infants with FXS. The current study focused on indices of visual attention, one of the earliest and most robust behavioral indicators of autism in idiopathic (non-FXS) autism. Analyses revealed lower HR variability, shallower HR decelerations, and prolonged look durations in 12-month old infants with FXS that were correlated with severity of autistic behavior but not mental age. PMID:21720726

Boys with fragile X syndrome: investigating temperament in early childhood.

PubMed

Low Kapalu, C M; Gartstein, M A

2016-09-01

Fragile X syndrome (FXS) is an x-linked genetic disorder that represents the most common hereditary cause of Intellectual Disability (ID). Very specific behavioural features (e.g. attention deficit hyperactivity disorder and stereotyped behaviour) are associated with FXS in adolescents and adults, yet research on temperament and behavioural characteristics in young children with FXS has been more limited and less conclusive. This study investigated temperament differences in young boys (3-7 years old) with FXS (N = 26) recruited from a national FXS centre and controls (N = 26) matched on age, gender and race. Compared with controls, boys with FXS exhibited less overall surgency/extraversion and effortful control. Boys with FXS also displayed significantly greater activity and shyness and less attentional focusing, inhibitory control, soothability and high intensity pleasure (tendency to enjoy intense/complex activities), relative to comparison children. A significant interaction between age and diagnosis (FXS or control) was observed for negative affectivity only. Attention difficulties commonly found in adolescents and adults with FXS appear to also be characteristic of young boys with FXS, as reflected by lower effortful control. Age-related findings concerning negative affectivity may be particularly significant, leading to improved intervention/preventative efforts. © 2016 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Exploring the zebra finch Taeniopygia guttata as a novel animal model for the speech-language deficit of fragile X syndrome.

PubMed

Winograd, Claudia; Ceman, Stephanie

2012-01-01

Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and presents with markedly atypical speech-language, likely due to impaired vocal learning. Although current models have been useful for studies of some aspects of FXS, zebra finch is the only tractable lab model for vocal learning. The neural circuits for vocal learning in the zebra finch have clear relationships to the pathways in the human brain that may be affected in FXS. Further, finch vocal learning may be quantified using software designed specifically for this purpose. Knockdown of the zebra finch FMR1 gene may ultimately enable novel tests of therapies that are modality-specific, using drugs or even social strategies, to ameliorate deficits in vocal development and function. In this chapter, we describe the utility of the zebra finch model and present a hypothesis for the role of FMRP in the developing neural circuitry for vocalization.

Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons

PubMed Central

2017-01-01

Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function. SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction. PMID:28887386

Absence of the Fragile X Mental Retardation Protein results in defects of RNA editing of neuronal mRNAs in mouse

PubMed Central

Filippini, Alice; Bonini, Daniela; Lacoux, Caroline; Zingariello, Maria; Sancillo, Laura; Bosisio, Daniela; Salvi, Valentina; Mingardi, Jessica; La Via, Luca; Zalfa, Francesca; Bagni, Claudia

2017-01-01

ABSTRACT The fragile X syndrome (FXS), the most common form of inherited intellectual disability, is due to the absence of FMRP, a protein regulating RNA metabolism. Recently, an unexpected function of FMRP in modulating the activity of Adenosine Deaminase Acting on RNA (ADAR) enzymes has been reported both in Drosophila and Zebrafish. ADARs are RNA-binding proteins that increase transcriptional complexity through a post-transcriptional mechanism called RNA editing. To evaluate the ADAR2-FMRP interaction in mammals we analyzed several RNA editing re-coding sites in the fmr1 knockout (KO) mice. Ex vivo and in vitro analysis revealed that absence of FMRP leads to an increase in the editing levels of brain specific mRNAs, indicating that FMRP might act as an inhibitor of editing activity. Proximity Ligation Assay (PLA) in mouse primary cortical neurons and in non-neuronal cells revealed that ADAR2 and FMRP co-localize in the nucleus. The ADAR2-FMRP co-localization was further observed by double-immunogold Electron Microscopy (EM) in the hippocampus. Moreover, ADAR2-FMRP interaction appeared to be RNA independent. Because changes in the editing pattern are associated with neuropsychiatric and neurodevelopmental disorders, we propose that the increased editing observed in the fmr1-KO mice might contribute to the FXS molecular phenotypes. PMID:28640668

Temperament Factor Structure in Fragile X Syndrome: The Children's Behavior Questionnaire

PubMed Central

Roberts, Jane E.; Tonnsen, Bridgette L.; Robinson, Marissa; McQuillin, Samuel D.; Hatton, Deborah D.

2014-01-01

Early patterns of temperament lay the foundation for a variety of developmental constructs such as self-regulation, psychopathology, and resilience. Children with fragile X syndrome (FXS) display unique patterns of temperament compared to age-matched clinical and non-clinical samples, and early patterns of temperament have been associated with later anxiety in this population. Despite these unique patterns in FXS and recent reports of atypical factor structure of temperament questionnaires in Williams Syndrome (Leyfer, John, Woodruff-Borden, & Mervis, 2012), no studies have examined the latent factor structure of temperament scales in FXS to ensure measurement validity in this sample. The present study used confirmatory factor analysis to examine the factor structure of a well-validated parent-reported temperament questionnaire, the Children's Behavior Questionnaire (Rothbart, Ahadi, Hershey, & Fisher, 2001), in a sample of 90 males with FXS ages 3-9 years. Our data produced a similar, but not identical, three-factor model that retained the original CBQ factors of negative affectivity, effortful control, and extraversion/surgency. In particular, our FXS sample demonstrated stronger factor loadings for fear and shyness than previously reported loadings in non-clinical samples, consistent with reports of poor social approach and elevated anxiety in this population. Although the original factor structure of the Children's Behavior Questionnaire is largely retained in children with FXS, differences in factor loading magnitudes may reflect phenotypic characteristics of the syndrome. These findings may inform future developmental and translational research efforts. PMID:24380785

Event-related potential alterations in fragile X syndrome

PubMed Central

Knoth, Inga S.; Lippé, Sarah

2012-01-01

Fragile X Syndrome (FXS) is the most common form of X-linked intellectual disability (ID), associated with a wide range of cognitive and behavioral impairments. FXS is caused by a trinucleotide repeat expansion in the FMR1 gene located on the X-chromosome. FMR1 is expected to prevent the expression of the “fragile X mental retardation protein (FMRP)”, which results in altered structural and functional development of the synapse, including a loss of synaptic plasticity. This review aims to unveil the contribution of electrophysiological signal studies for the understanding of the information processing impairments in FXS patients. We discuss relevant event-related potential (ERP) studies conducted with full mutation FXS patients and clinical populations sharing symptoms with FXS in a developmental perspective. Specific deviances found in FXS ERP profiles are described. Alterations are reported in N1, P2, Mismatch Negativity (MMN), N2, and P3 components in FXS compared to healthy controls. Particularly, deviances in N1 and P2 amplitude seem to be specific to FXS. The presented results suggest a cascade of impaired information processes that are in line with symptoms and anatomical findings in FXS. PMID:23015788

Operational properties of fluctuation X-ray scattering data

DOE PAGES

Malmerberg, Erik; Kerfeld, Cheryl A.; Zwart, Petrus H.

2015-03-20

X-ray scattering images collected on timescales shorter than rotation diffusion times using a (partially) coherent beam result in a significant increase in information content in the scattered data. These measurements, named fluctuation X-ray scattering (FXS), are typically performed on an X-ray free-electron laser (XFEL) and can provide fundamental insights into the structure of biological molecules, engineered nanoparticles or energy-related mesoscopic materials beyond what can be obtained with standard X-ray scattering techniques. In order to understand, use and validate experimental FXS data, the availability of basic data characteristics and operational properties is essential, but has been absent up to this point.more » In this communication, an intuitive view of the nature of FXS data and their properties is provided, the effect of FXS data on the derived structural models is highlighted, and generalizations of the Guinier and Porod laws that can ultimately be used to plan experiments and assess the quality of experimental data are presented.« less

Toward fulfilling the promise of molecular medicine in fragile X syndrome.

PubMed

Krueger, Dilja D; Bear, Mark F

2011-01-01

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism.

Understanding fragile X syndrome from a mother's perspective: Challenges and resilience

PubMed Central

Weber, Chantel Lynette

2016-01-01

The purpose of this study is to communicate findings from a case study on a South African mother with three children diagnosed with full mutation fragile X syndrome (FXS). The participant is an unaffected carrier of FXS. Research has shown that mothers of children with FXS often experience high levels of parenting stress and low levels of psychological well-being. However, observations made have piqued curiosity about their positivity and determination to carry on each day raising children diagnosed with FXS. The aim is to develop a better understanding of the manner in which a mother of children with FXS make sense of her situation, to gain further insight into the specific resilience processes she acquired. A qualitative case study approach was followed, gathering data through semi-structured interviews based on open-ended questions. The findings offer new insights into a South African mother's life raising children with FXS. Even though there is very limited support and little awareness of FXS in South Africa, she still found ways to seek help, and find solutions to every day challenges. The study conclusions discourage blind stereotyping of mothers of children with FXS as vulnerable only. Future research should concentrate on promoting awareness, education, advocacy, and support for individuals with FXS in South Africa. PMID:27104339

Sensory processing in autism spectrum disorders and Fragile X syndrome—From the clinic to animal models

PubMed Central

Sinclair, D.; Oranje, B.; Razak, K.A.; Siegel, S.J.; Schmid, S.

2017-01-01

Brains are constantly flooded with sensory information that needs to be filtered at the pre-attentional level and integrated into endogenous activity in order to allow for detection of salient information and an appropriate behavioral response. People with Autism Spectrum Disorder (ASD) or Fragile X Syndrome (FXS) are often over- or under-reactive to stimulation, leading to a wide range of behavioral symptoms. This altered sensitivity may be caused by disrupted sensory processing, signal integration and/or gating, and is often being neglected. Here, we review translational experimental approaches that are used to investigate sensory processing in humans with ASD and FXS, and in relevant rodent models. This includes electroencephalographic measurement of event related potentials, neural oscillations and mismatch negativity, as well as habituation and pre-pulse inhibition of startle. We outline robust evidence of disrupted sensory processing in individuals with ASD and FXS, and in respective animal models, focusing on the auditory sensory domain. Animal models provide an excellent opportunity to examine common mechanisms of sensory pathophysiology in order to develop therapeutics. PMID:27235081

Modeling Fragile X Syndrome in Drosophila

PubMed Central

Drozd, Małgorzata; Bardoni, Barbara; Capovilla, Maria

2018-01-01

Intellectual disability (ID) and autism are hallmarks of Fragile X Syndrome (FXS), a hereditary neurodevelopmental disorder. The gene responsible for FXS is Fragile X Mental Retardation gene 1 (FMR1) encoding the Fragile X Mental Retardation Protein (FMRP), an RNA-binding protein involved in RNA metabolism and modulating the expression level of many targets. Most cases of FXS are caused by silencing of FMR1 due to CGG expansions in the 5′-UTR of the gene. Humans also carry the FXR1 and FXR2 paralogs of FMR1 while flies have only one FMR1 gene, here called dFMR1, sharing the same level of sequence homology with all three human genes, but functionally most similar to FMR1. This enables a much easier approach for FMR1 genetic studies. Drosophila has been widely used to investigate FMR1 functions at genetic, cellular, and molecular levels since dFMR1 mutants have many phenotypes in common with the wide spectrum of FMR1 functions that underlay the disease. In this review, we present very recent Drosophila studies investigating FMRP functions at genetic, cellular, molecular, and electrophysiological levels in addition to research on pharmacological treatments in the fly model. These studies have the potential to aid the discovery of pharmacological therapies for FXS. PMID:29713264

Altered Brain Network Segregation in Fragile X Syndrome Revealed by Structural Connectomics.

PubMed

Bruno, Jennifer Lynn; Hosseini, S M Hadi; Saggar, Manish; Quintin, Eve-Marie; Raman, Mira Michelle; Reiss, Allan L

2017-03-01

Fragile X syndrome (FXS), the most common inherited cause of intellectual disability and autism spectrum disorder, is associated with significant behavioral, social, and neurocognitive deficits. Understanding structural brain network topology in FXS provides an important link between neurobiological and behavioral/cognitive symptoms of this disorder. We investigated the connectome via whole-brain structural networks created from group-level morphological correlations. Participants included 100 individuals: 50 with FXS and 50 with typical development, age 11-23 years. Results indicated alterations in topological properties of structural brain networks in individuals with FXS. Significantly reduced small-world index indicates a shift in the balance between network segregation and integration and significantly reduced clustering coefficient suggests that reduced local segregation shifted this balance. Caudate and amygdala were less interactive in the FXS network further highlighting the importance of subcortical region alterations in the neurobiological signature of FXS. Modularity analysis indicates that FXS and typically developing groups' networks decompose into different sets of interconnected sub networks, potentially indicative of aberrant local interconnectivity in individuals with FXS. These findings advance our understanding of the effects of fragile X mental retardation protein on large-scale brain networks and could be used to develop a connectome-level biological signature for FXS. © The Author 2016. Published by Oxford University Press. All rights reserved. For Permissions, please e-mail: journals.permissions@oup.com.

Blink rate in boys with fragile X syndrome: preliminary evidence for altered dopamine function.

PubMed

Roberts, J E; Symons, F J; Johnson, A-M; Hatton, D D; Boccia, M L

2005-09-01

Dopamine, a neurotransmitter involved in motor and cognitive functioning, can be non-invasively measured via observation of spontaneous blink rates. Blink rates have been studied in a number of clinical conditions including schizophrenia, autism, Parkinsons, and attention deficit/hyperactivity disorder with results implicating either hyper or hypo dopaminergic states. This study examined spontaneous blink rate in boys with fragile X syndrome (FXS). Blink rates of boys (4-8 years old) with FXS (n = 6) were compared with those of age-matched typically developing boys (n = 6) during active and passive tasks. Blink rates (blinks per minute) for each task were compared between the two groups. Then, the relation between blink measures and core FXS-related features [problem behaviours, arousal, fmr 1 protein (FMRP)] were examined within the group of boys with FXS. Blink rate in boys with FXS was significantly higher than typically developing boys during passive tasks. Within the FXS group, there were significant correlations between blink rate and problem behaviours and physiological arousal (i.e. heart activity) but not with FMRP. Observed differences in spontaneous blink rate between boys with and without FXS and the relation between blink rate and physiological and behavioural measures in boys with FXS suggests that further work examining dopamine dysfunction as a factor in the pathophysiology of FXS may be warranted.

Fragile X Mental Retardation Protein Restricts Small Dye Iontophoresis Entry into Central Neurons.

PubMed

Kennedy, Tyler; Broadie, Kendal

2017-10-11

Fragile X mental retardation protein (FMRP) loss causes Fragile X syndrome (FXS), a major disorder characterized by autism, intellectual disability, hyperactivity, and seizures. FMRP is both an RNA- and channel-binding regulator, with critical roles in neural circuit formation and function. However, it remains unclear how these FMRP activities relate to each other and how dysfunction in their absence underlies FXS neurological symptoms. In testing circuit level defects in the Drosophila FXS model, we discovered a completely unexpected and highly robust neuronal dye iontophoresis phenotype in the well mapped giant fiber (GF) circuit. Controlled dye injection into the GF interneuron results in a dramatic increase in dye uptake in neurons lacking FMRP. Transgenic wild-type FMRP reintroduction rescues the mutant defect, demonstrating a specific FMRP requirement. This phenotype affects only small dyes, but is independent of dye charge polarity. Surprisingly, the elevated dye iontophoresis persists in shaking B mutants that eliminate gap junctions and dye coupling among GF circuit neurons. We therefore used a wide range of manipulations to investigate the dye uptake defect, including timed injection series, pharmacology and ion replacement, and optogenetic activity studies. The results show that FMRP strongly limits the rate of dye entry via a cytosolic mechanism. This study reveals an unexpected new phenotype in a physical property of central neurons lacking FMRP that could underlie aspects of FXS disruption of neural function. SIGNIFICANCE STATEMENT FXS is a leading heritable cause of intellectual disability and autism spectrum disorders. Although researchers established the causal link with FMRP loss >;25 years ago, studies continue to reveal diverse FMRP functions. The Drosophila FXS model is key to discovering new FMRP roles, because of its genetic malleability and individually identified neuron maps. Taking advantage of a well characterized Drosophila neural circuit, we discovered that neurons lacking FMRP take up dramatically more current-injected small dye. After examining many neuronal properties, we determined that this dye defect is cytoplasmic and occurs due to a highly elevated dye iontophoresis rate. We also report several new factors affecting neuron dye uptake. Understanding how FMRP regulates iontophoresis should reveal new molecular factors underpinning FXS dysfunction. Copyright © 2017 the authors 0270-6474/17/379844-15$15.00/0.

Brief Review of Current Research in FXS: Implications for Treatment with Psychotropic Medication

ERIC Educational Resources Information Center

Valdovinos, Maria G.

2007-01-01

The purpose of this paper is to provide a brief review of current research in fragile X syndrome (FXS) with regards to the morphology and behavioral phenotype associated with FXS and the use of psychotropic medication for the treatment of behavior problems (e.g., aggression) often seen in FXS (full mutation). The lack of production of the fragile…

Cognition and Lobar Morphology in Full Mutation Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Meguid, Nagwa A.; Fahim, Cherine; Sami, Rasha; Nashaat, Neveen H.; Yoon, Uicheul; Anwar, Mona; El-Dessouky, Hosam M.; Shahine, Elham A.; Ibrahim, Ahmed Samir; Mancini-Marie, Adham; Evans, Alan C.

2012-01-01

The aims of the present study are twofold: (1) to examine cortical morphology (CM) associated with alterations in cognition in fragile X syndrome (FXS); (2) to characterize the CM profile of FXS versus FXS with an autism diagnosis (FXS+Aut) as a preliminary attempt to further elucidate the behavioral distinctions between the two sub-groups. We…

Early social communication in infants with fragile X syndrome and infant siblings of children with autism spectrum disorder.

PubMed

Hahn, Laura J; Brady, Nancy C; McCary, Lindsay; Rague, Lisa; Roberts, Jane E

2017-12-01

Little research in fragile X syndrome (FXS) has prospectively examined early social communication. To compare early social communication in infants with FXS, infant siblings of children with autism spectrum disorder (ASIBs), and typically developing (TD) infants. Participants were 18 infants with FXS, 21 ASIBs, and 22 TD infants between 7.5-14.5 months. Social communication was coded using the Communication Complexity Scale during the administration of Autism Observation Scale for Infants. Descriptively different patterns were seen across the three groups. Overall infants with FXS had lower social communication than ASIBs or TD infants when controlling for nonverbal cognitive abilities. However, infants with FXS had similar levels of social communication as ASIBs or TD infants during peek-a-boo. No differences were observed between ASIBs and TD infants. For all infants, higher social communication was related to lower ASD risk. Findings provide insight into the developmental course of social communication in FXS. The dynamic nature of social games may help to stimulate communication in infants with FXS. Language interventions with a strong social component may be particularly effective for promoting language development in FXS. Copyright © 2017 Elsevier Ltd. All rights reserved.

Stranger Fear and Early Risk for Social Anxiety in Preschoolers with Fragile X Syndrome Contrasted to Autism Spectrum Disorder

ERIC Educational Resources Information Center

Scherr, Jessica F.; Hogan, Abigail L.; Hatton, Deborah; Roberts, Jane E.

2017-01-01

This study investigated behavioral indicators of social fear in preschool boys with fragile X syndrome (FXS) with a low degree of autism spectrum disorder (ASD) symptoms (FXS-Low; n = 29), FXS with elevated ASD symptoms (FXS-High; n = 25), idiopathic ASD (iASD; n = 11), and typical development (TD; n = 36). Gaze avoidance, escape behaviors, and…

Cognitive, Language and Social-Cognitive Skills of Individuals with Fragile X Syndrome with and without Autism

ERIC Educational Resources Information Center

Lewis, Pamela; Abbeduto, L.; Murphy, M.; Richmond, E.; Giles, N.; Bruno, L.; Schroeder, S.

2006-01-01

Background: It is not known whether those with co-morbid fragile X syndrome (FXS) and autism represent a distinct subtype of FXS; whether the especially severe cognitive delays seen in studies of young children with co-morbid FXS and autism compared with those with only FXS continue into adolescence and young adulthood; and whether autism in those…

Toward Fulfilling the Promise of Molecular Medicine in Fragile X Syndrome

PubMed Central

Krueger, Dilja D.; Bear, Mark F.

2011-01-01

Fragile X syndrome (FXS) is the most common inherited form of mental retardation and a leading known cause of autism. It is caused by loss of expression of the fragile X mental retardation protein (FMRP), an RNA-binding protein that negatively regulates protein synthesis. In neurons, multiple lines of evidence suggest that protein synthesis at synapses is triggered by activation of group 1 metabotropic glutamate receptors (Gp1 mGluRs) and that many functional consequences of activating these receptors are altered in the absence of FMRP. These observations have led to the theory that exaggerated protein synthesis downstream of Gp1 mGluRs is a core pathogenic mechanism in FXS. This excess can be corrected by reducing signaling by Gp1 mGluRs, and numerous studies have shown that inhibition of mGluR5, in particular, can ameliorate multiple mutant phenotypes in animal models of FXS. Clinical trials based on this therapeutic strategy are currently under way. FXS is therefore poised to be the first neurobehavioral disorder in which corrective treatments have been developed from the bottom up: from gene identification to pathophysiology in animals to novel therapeutics in humans. The insights gained from FXS and other autism-related single-gene disorders may also assist in identifying molecular mechanisms and potential treatment approaches for idiopathic autism. PMID:21090964

Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome.

PubMed

Erickson, Craig A; Wink, Logan K; Ray, Balmiki; Early, Maureen C; Stiegelmeyer, Elizabeth; Mathieu-Frasier, Lauren; Patrick, Vanessa; Lahiri, Debomoy K; McDougle, Christopher J

2013-07-01

Fragile X syndrome (FXS) is an inherited form of developmental disability and a single gene cause of autism. As a disorder with increasingly understood pathophysiology, FXS is a model form of developmental disability for targeted drug development efforts. Preclinical animal model findings have focused targeted drug treatment development in FXS on an imbalance between excessive glutamate and deficient gamma-aminobutyric acid (GABA) neurotransmission. We conducted a prospective open-label 10-week trial of acamprosate in 12 youth aged 6-17 years (mean age: 11.9 years) with FXS. Acamprosate use (mean dose: 1,054  ±  422 mg/day) was associated with treatment response (defined by a Clinical Global Impressions Improvement (CGI-I) scale score of "very much improved" or "much improved") in nine of 12 (75 %) subjects. Improvement was noted in social behavior and inattention/hyperactivity using multiple standard behavioral outcome measures. No significant adverse effects or changes in vital signs, including weight or laboratory measures, occurred during treatment with acamprosate. Additionally, pre- and post-treatment blood biomarker analyses looking at brain-derived neurotrophic factor (BDNF) levels found a significant increase in BDNF with treatment. In our pilot sample, treatment response did not correlate with change in BDNF with treatment. Acamprosate was generally safe and well tolerated and was associated with a significant improvement in social behavior and a reduction in inattention/hyperactivity. The increase in BDNF that occurred with treatment may be a useful pharmacodynamic marker in future acamprosate studies. Given these findings, a double-blind, placebo-controlled study of acamprosate in youth with FXS is warranted.

Elimination disorders in persons with Prader-Willi and Fragile-X syndromes.

PubMed

Equit, Monika; Piro-Hussong, Aline; Niemczyk, Justine; Curfs, Leopold; von Gontard, Alexander

2013-09-01

Elimination disorders are common in typically developing children. Only few studies have addressed elimination disorders in persons with intellectual disability (ID)-and even fewer studies in those with specific syndromes. The aim of the study was to investigate the rates of elimination disorders and behavioral symptoms in persons with Prader-Willi (PWS) and Fragile-X syndromes (FXS) in a large sample. Three hundred fifty-seven persons with PWS or FXS were recruited through parent self-help groups. A questionnaire regarding elimination symptoms, as well as the child behavior checklist (CBCL)/young adult behavior checklist (YABCL) were filled out by parents or caregivers. The sample included 191 persons with PWS (54.5% male) with a mean age of 20.0 years and 166 persons with FXS (92.2% male) with a mean age of 15.4 years. Persons with FXS were significantly more often affected by elimination disorders. 29.3% of persons with PWS and 48.8% of persons with FXS had at least one elimination disorder. Persons with FXS also had more often DUI (29.5% vs. 12.0%) and FI (28.9% vs. 12.6%). Rates of NE were similar in both groups (22.0% in PWS vs. 28.9% in FXS). Young adults with PWS had more behavioral symptoms in the clinical range (70.8% vs. 48.3%). Incontinence and behavioral symptoms were significantly associated in persons with FXS. NE, DUI, and FI are very common in persons with FXS and PWS and are associated with other behavioral symptoms in persons with FXS. They persist into adulthood. Early assessment and treatment are recommended. Copyright © 2012 Wiley Periodicals, Inc.

The FMR1 promoter is selectively hydroxymethylated in primary neurons of fragile X syndrome patients.

PubMed

Esanov, Rustam; Andrade, Nadja S; Bennison, Sarah; Wahlestedt, Claes; Zeier, Zane

2016-11-15

Fragile X syndrome (FXS) results from a repeat expansion mutation near the FMR1 gene promoter and is the most common form of heritable intellectual disability and autism. Full mutations larger than 200 CGG repeats trigger FMR1 heterochromatinization and loss of gene expression, which is primarily responsible for the pathological features of FXS . In contrast, smaller pre-mutations of 55–200 CGG are associated with FMR1 overexpression and Fragile X-associated tremor/ataxia syndrome (FXTAS), a late-onset neurodegenerative condition. While the role of 5-methylcytosine (5mC) in FMR1 gene silencing has been studied extensively, the role of 5-hydroxymethylation (5hmC), a newly discovered epigenetic mark produced through active DNA demethylation, has not been previously investigated in FXS neurons. Here, we used two complementary epigenetic assays, 5hmC sensitive restriction digest and ten-eleven translocation-assisted bisulfite pyrosequencing, to quantify FMR1 5mC and 5hmC levels. We observed increased levels of 5hmC at the FMR1 promoter in FXS patient brains with full-mutations relative to pre-mutation carriers and unaffected controls. In addition, we found that 5hmC enrichment at the FMR1 locus in FXS cells is specific to neurons by utilizing a nuclei sorting technique to separate neuronal and glial DNA fractions from post-mortem brain tissues. This FMR1 5hmC enrichment was not present in cellular models of FXS including fibroblasts, lymphocytes and reprogrammed neurons, indicating they do not fully recapitulate this epigenetic feature of disease. Future studies could investigate the potential to leverage this epigenetic pathway to restore FMR1 expression and discern whether levels of 5hmC correlate with phenotypic severity.

Adaptive behaviour of Chinese boys with fragile X syndrome.

PubMed

Zhu, Z; Li, W; Zhan, J; Hu, L; Wu, L; Zhao, Z

2016-01-01

Adaptive behaviour is closely related to quality of life in children with intellectual disability (ID), but little is known about the adaptive behaviour of children with fragile X syndrome (FXS) in China. In boys with FXS, the adaptive behaviours in six domains, including self-dependence, locomotion, work skills, communication, socialisation and self-management, were assessed by the Infants-Junior Middle School Students Social-life Abilities Scale. In addition, we compared the adaptive skills of boys with FXS to those of three control groups of boys, including boys with Down syndrome (DS) and typically developing (TD) boys matched by chronological age (CA) or mental age (MA). The profile of the adaptive behaviour of boys with FXS is discussed in detail. Compared to boys with DS, boys with FXS obtained lower scores in three domains in adaptive behaviour, including work skills, socialisation and self-management skills; boys with FXS had better scores in self-dependence and locomotion skills than boys matched for MA; as expected, boys with FXS had significantly poorer adaptive skills in all six domains assessed compared to CA boys. The development of adaptive skills in boys with FXS was worse than that of boys with DS. The profile of the adaptive behaviour of boys with FXS establishes a basis for the development of targeted interventions to promote social development in this population. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Resting-state fMRI study of patients with fragile X syndrome

NASA Astrophysics Data System (ADS)

Isanova, E.; Petrovskiy, E.; Savelov, A.; Yudkin, D.; Tulupov, A.

2017-08-01

The study aimed to assess the neural activity of different brain regions in patients with fragile X syndrome (FXS) and the healthy volunteers by resting-state functional magnetic resonance imaging (fMRI) on a 1.5 T MRI Achieva scanner (Philips). Results: The fMRI study showed a DMN of brain function in patients with FXS, as well as in the healthy volunteers. Furthermore, it was found that a default mode network of the brain in patients with FXS and healthy volunteers does not have statistically significant differences (p>0.05), which may indicate that the basal activity of neurons in patients with FXS is not reduced. In addition, we have found a significant (p<0.001) increase in the FC within the right inferior parietal and right angular gyrus in the resting state in patients with FXS. Conclusion: New data of functional status of the brain in patients with FXS were received. The significant increase in the resting state functional connectivity within the right inferior parietal and right angular gyrus (p<0.001) in patients with FXS was found.

Fragile X syndrome: A review of clinical management

PubMed Central

Lozano, Reymundo; Azarang, Atoosa; Wilaisakditipakorn, Tanaporn; Hagerman, Randi J

2016-01-01

Summary The fragile X mental retardation 1 gene, which codes for the fragile X mental retardation 1 protein, usually has 5 to 40 CGG repeats in the 5′ untranslated promoter. The full mutation is the almost always the cause of fragile X syndrome (FXS). The prevalence of FXS is about 1 in 4,000 to 1 in 7,000 in the general population although the prevalence varies in different regions of the world. FXS is the most common inherited cause of intellectual disability and autism. The understanding of the neurobiology of FXS has led to many targeted treatments, but none have cured this disorder. The treatment of the medical problems and associated behaviors remain the most useful intervention for children with FXS. In this review, we focus on the non-pharmacological and pharmacological management of medical and behavioral problems associated with FXS as well as current recommendations for follow-up and surveillance. PMID:27672537

Identification of Fragile X Syndrome-Specific Molecular Markers in Human Fibroblasts: A Useful Model to Test the Efficacy of Therapeutic Drugs

PubMed Central

Kumari, Daman; Bhattacharya, Aditi; Nadel, Jeffrey; Moulton, Kristen; Zeak, Nicole M.; Glicksman, Anne; Dobkin, Carl; Brick, David J.; Schwartz, Philip H.; Smith, Carolyn B.; Klann, Eric; Usdin, Karen

2014-01-01

Fragile X Syndrome (FXS) is the most frequent cause of inherited intellectual disability and autism. It is caused by the absence of the fragile X mental retardation 1 (FMR1) gene product, FMRP, an RNA-binding protein involved in the regulation of translation of a subset of brain mRNAs. In Fmr1 knockout (KO) mice, the absence of FMRP results in elevated protein synthesis in the brain as well as increased signaling of many translational regulators. Whether protein synthesis is also dysregulated in FXS patients is not firmly established. Here, we demonstrate that fibroblasts from FXS patients have significantly elevated rates of basal protein synthesis along with increased levels of phosphorylated mechanistic target of rapamycin (p-mTOR), phosphorylated extracellular signal regulated kinase 1/2 (p-ERK 1/2) and phosphorylated p70 ribosomal S6 kinase 1 (p-S6K1). Treatment with small molecules that inhibit S6K1, and a known FMRP target, phosphoinositide 3-kinase (PI3K) catalytic subunit p110β, lowered the rates of protein synthesis in both control and patient fibroblasts. Our data thus demonstrate that fibroblasts from FXS patients may be a useful in vitro model to test the efficacy and toxicity of potential therapeutics prior to clinical trials, as well as for drug screening and designing personalized treatment approaches. PMID:25224527

High-Throughput Screening Using iPSC-Derived Neuronal Progenitors to Identify Compounds Counteracting Epigenetic Gene Silencing in Fragile X Syndrome.

PubMed

Kaufmann, Markus; Schuffenhauer, Ansgar; Fruh, Isabelle; Klein, Jessica; Thiemeyer, Anke; Rigo, Pierre; Gomez-Mancilla, Baltazar; Heidinger-Millot, Valerie; Bouwmeester, Tewis; Schopfer, Ulrich; Mueller, Matthias; Fodor, Barna D; Cobos-Correa, Amanda

2015-10-01

Fragile X syndrome (FXS) is the most common form of inherited mental retardation, and it is caused in most of cases by epigenetic silencing of the Fmr1 gene. Today, no specific therapy exists for FXS, and current treatments are only directed to improve behavioral symptoms. Neuronal progenitors derived from FXS patient induced pluripotent stem cells (iPSCs) represent a unique model to study the disease and develop assays for large-scale drug discovery screens since they conserve the Fmr1 gene silenced within the disease context. We have established a high-content imaging assay to run a large-scale phenotypic screen aimed to identify compounds that reactivate the silenced Fmr1 gene. A set of 50,000 compounds was tested, including modulators of several epigenetic targets. We describe an integrated drug discovery model comprising iPSC generation, culture scale-up, and quality control and screening with a very sensitive high-content imaging assay assisted by single-cell image analysis and multiparametric data analysis based on machine learning algorithms. The screening identified several compounds that induced a weak expression of fragile X mental retardation protein (FMRP) and thus sets the basis for further large-scale screens to find candidate drugs or targets tackling the underlying mechanism of FXS with potential for therapeutic intervention. © 2015 Society for Laboratory Automation and Screening.

Social approach and emotion recognition in fragile X syndrome.

PubMed

Williams, Tracey A; Porter, Melanie A; Langdon, Robyn

2014-03-01

Evidence is emerging that individuals with Fragile X syndrome (FXS) display emotion recognition deficits, which may contribute to their significant social difficulties. The current study investigated the emotion recognition abilities, and social approachability judgments, of FXS individuals when processing emotional stimuli. Relative to chronological age- (CA-) and mental age- (MA-) matched controls, the FXS group performed significantly more poorly on the emotion recognition tasks, and displayed a bias towards detecting negative emotions. Moreover, after controlling for emotion recognition deficits, the FXS group displayed significantly reduced ratings of social approachability. These findings suggest that a social anxiety pattern, rather than poor socioemotional processing, may best explain the social avoidance observed in FXS.

Effects of computerized match-to-sample training on emergent fraction-decimal relations in individuals with fragile X syndrome.

PubMed

Hammond, Jennifer L; Hirt, Melissa; Hall, Scott S

2012-01-01

Individuals diagnosed with fragile X syndrome (FXS), the most common known form of inherited intellectual disability, are reported to exhibit considerable deficits in mathematical skills that are often attributed to brain-based abnormalities associated with the syndrome. We examined whether participants with FXS would display emergent fraction-decimal relations following brief, intensive match-to-sample training on baseline relations. The performance profiles on tests of symmetry and transitivity/equivalence of 11 participants with FXS, aged 10-23 years, following baseline match-to-sample training were compared to those of 11 age- and IQ-matched controls with idiopathic developmental disability. The results showed that both groups of participants showed significant improvements in the baseline (trained) relations, as expected. However, participants with FXS failed to show significant improvements in the (untrained) symmetry and transitivity/equivalence relations compared to those in the control group. A categorical analysis of the data indicated that five participants with FXS and eight controls showed at least "intermediate" emergence of symmetry relations, whereas one individual with FXS and three controls showed at least intermediate emergence of transitivity/equivalence relations. A correlation analysis of the data indicated that improvements in the symmetry relations were significantly associated with improvements in the transitivity/equivalence relations in the control group (r=.69, p=.018), but this was not the case in the FXS group (r=.34, p>.05). Participant IQ was significantly associated with improvements in the symmetry relations in individuals with FXS (r=.60, p=.049), but not in controls (r=.21, p>.05). Taken together, these results suggest that brief, computerized match-to-sample training may produce emergent mathematical relations for a subset of children with FXS and developmental disabilities. However, the ability of individuals with FXS to form transitivity/equivalence relations may be impaired relative to those with idiopathic developmental disabilities, which may be attributed to neurodevelopmental variables associated with the syndrome. Copyright © 2011 Elsevier Ltd. All rights reserved.

High-Throughput Screening to Identify Compounds That Increase Fragile X Mental Retardation Protein Expression in Neural Stem Cells Differentiated From Fragile X Syndrome Patient-Derived Induced Pluripotent Stem Cells.

PubMed

Kumari, Daman; Swaroop, Manju; Southall, Noel; Huang, Wenwei; Zheng, Wei; Usdin, Karen

2015-07-01

: Fragile X syndrome (FXS), the most common form of inherited cognitive disability, is caused by a deficiency of the fragile X mental retardation protein (FMRP). In most patients, the absence of FMRP is due to an aberrant transcriptional silencing of the fragile X mental retardation 1 (FMR1) gene. FXS has no cure, and the available treatments only provide symptomatic relief. Given that FMR1 gene silencing in FXS patient cells can be partially reversed by treatment with compounds that target repressive epigenetic marks, restoring FMRP expression could be one approach for the treatment of FXS. We describe a homogeneous and highly sensitive time-resolved fluorescence resonance energy transfer assay for FMRP detection in a 1,536-well plate format. Using neural stem cells differentiated from an FXS patient-derived induced pluripotent stem cell (iPSC) line that does not express any FMRP, we screened a collection of approximately 5,000 known tool compounds and approved drugs using this FMRP assay and identified 6 compounds that modestly increase FMR1 gene expression in FXS patient cells. Although none of these compounds resulted in clinically relevant levels of FMR1 mRNA, our data provide proof of principle that this assay combined with FXS patient-derived neural stem cells can be used in a high-throughput format to identify better lead compounds for FXS drug development. In this study, a specific and sensitive fluorescence resonance energy transfer-based assay for fragile X mental retardation protein detection was developed and optimized for high-throughput screening (HTS) of compound libraries using fragile X syndrome (FXS) patient-derived neural stem cells. The data suggest that this HTS format will be useful for the identification of better lead compounds for developing new therapeutics for FXS. This assay can also be adapted for FMRP detection in clinical and research settings. ©AlphaMed Press.

Down Syndrome and Fragile X Syndrome in a Colombian Woman: Case Report.

PubMed

Saldarriaga, Wilmar; Ruiz, Fabian Andres; Tassone, Flora; Hagerman, Randi

2017-09-01

Down syndrome (DS) and Fragile X syndrome (FXS) are the major genetic causes of intellectual disabilities. Here, we present a case of a 32-year-old woman with the diagnosis of both FXS and DS. She is the daughter of a 47-year-old pre-mutation woman who also has three sons with FXS. Cytogenetic testing detected the presence of a complete trisomy 21. A combination of PCR and Southern blot analysis was utilized to document the presence of the FMR1 full mutation. The patient has physical characteristics and behavioural disturbances typical of both FXS and DS, which were confirmed by molecular testing. Her treatment plan included a trial of sertraline because of the severity of her shyness and lack of language. She had an excellent response to sertraline with improvement in shyness and social interactions, particularly with family members. In this study, we report the case of a woman with both FXS and DS, which is the fifth case of FXS and DS in the world's literature. The patient is from Ricaurte, a small town in Colombia, South America, where there is the world's highest prevalence for FXS. © 2016 John Wiley & Sons Ltd.

Integrated transcriptome analysis of human iPS cells derived from a fragile X syndrome patient during neuronal differentiation.

PubMed

Lu, Ping; Chen, Xiaolong; Feng, Yun; Zeng, Qiao; Jiang, Cizhong; Zhu, Xianmin; Fan, Guoping; Xue, Zhigang

2016-11-01

Fragile X syndrome (FXS) patients carry the expansion of over 200 CGG repeats at the promoter of fragile X mental retardation 1 (FMR1), leading to decreased or absent expression of its encoded fragile X mental retardation protein (FMRP). However, the global transcriptional alteration by FMRP deficiency has not been well characterized at single nucleotide resolution, i.e., RNA-seq. Here, we performed in-vitro neuronal differentiation of human induced pluripotent stem (iPS) cells that were derived from fibroblasts of a FXS patient (FXS-iPSC). We then performed RNA-seq and examined the transcriptional misregulation at each intermediate stage during in-vitro differentiation of FXS-iPSC into neurons. After thoroughly analyzing the transcriptomic data and integrating them with those from other platforms, we found up-regulation of many genes encoding TFs for neuronal differentiation (WNT1, BMP4, POU3F4, TFAP2C, and PAX3), down-regulation of potassium channels (KCNA1, KCNC3, KCNG2, KCNIP4, KCNJ3, KCNK9, and KCNT1) and altered temporal regulation of SHANK1 and NNAT in FXS-iPSC derived neurons, indicating impaired neuronal differentiation and function in FXS patients. In conclusion, we demonstrated that the FMRP deficiency in FXS patients has significant impact on the gene expression patterns during development, which will help to discover potential targeting candidates for the cure of FXS symptoms.

Family Communication and Cascade Testing for Fragile X Syndrome.

PubMed

Raspa, Melissa; Edwards, Anne; Wheeler, Anne C; Bishop, Ellen; Bailey, Donald B

2016-10-01

A total of 679 families who had at least one child with fragile X syndrome (FXS) were recruited from a research registry to participate in a survey examining cascade testing and communication about FXS. Families had a total of 1117 children (804 males, 313 females). Most families (84 %) had tested all of their children. The main reason for not testing, which did not differ by gender or age of the child, was that the child did not show signs of FXS (68 %). Families talked with their children about FXS occasionally (47 %) although 16 % said they do not talk about it. Most families (66 %) had told their children their FXS status, with males and those with the premutation being less likely to be told test results. Of those that did not, 46 % said that they would tell their child when they were old enough to understand, whereas 34 % had either decided they would not tell or were not sure if or when they were going to tell. About a quarter of respondents (28 %) indicated that no extended family members had been tested, with income and communication about FXS being the strongest predictors. Results from this large scale survey provide important data on how families communicate about FXS and reasons testing is or is not sought. This information can be used by genetic counsellors in providing follow-up to families after a FXS diagnosis.

Trajectories of Early Brain Volume Development in Fragile X and Autism RH: Trajectory of Brain Volume in Fragile X

PubMed Central

Hazlett, Heather Cody; Poe, Michele D.; Lightbody, Amy A.; Styner, Martin; MacFall, James R.; Reiss, Allan L.; Piven, Joseph

2012-01-01

Objective To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared to a comparison group (controls) and a group with idiopathic autism. Method The study included 53 boys between 18–42 months of age with FXS, 68 boys with idiopathic autism (ASD), and a comparison group of 50 typically-developing and developmentally-delayed controls. We examined structural brain volumes using magnetic resonance imaging (MRI) across two timepoints between ages 2–3 and 4–5 years and examined total brain volumes and regional (lobar) tissue volumes. Additionally, we studied a selected group of subcortical structures implicated in the behavioral features of FXS (e.g., basal ganglia, hippocampus, amygdala). Results Children with FXS had greater global brain volumes compared to controls, but were not different than children with idiopathic autism, and the rate of brain growth between ages 2 and 5 paralleled that seen in controls. In contrast to the children with idiopathic autism who had generalized cortical lobe enlargement, the children with FXS showed a specific enlargement in temporal lobe white matter, cerebellar gray matter, and caudate nucleus, but significantly smaller amygdala. Conclusions This structural longitudinal MRI study of preschoolers with FXS observed generalized brain overgrowth in FXS compared to controls, evident at age 2 and maintained across ages 4–5. We also find different patterns of brain growth that distinguishes boys with FXS from children with idiopathic autism. PMID:22917205

Open-Label Memantine in Fragile X Syndrome

ERIC Educational Resources Information Center

Erickson, Craig A.; Mullett, Jennifer E.; McDougle, Christopher J.

2009-01-01

Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). The purpose of this pilot study was to examine the effectiveness and tolerability of memantine for a number of target symptoms associated with FXS. Medical records describing open-label treatment with memantine in 6 patients with FXS and a comorbid…

Autism spectrum disorder symptoms in infants with fragile X syndrome: A prospective case series

PubMed Central

Hogan, Abigail L.; Caravella, Kelly E.; Ezell, Jordan; Rague, Lisa; Hills, Kimberly; Roberts, Jane E.

2017-01-01

No studies to date have prospectively examined early autism spectrum disorder (ASD) markers in infants with fragile X syndrome (FXS), who are at elevated risk for ASD. This paper describes the developmental profiles of eight infants with FXS from 9 to 24 months of age. Four meet diagnostic criteria for ASD at 24 months of age, and four do not. Trends in these case studies suggest that early social-communicative deficits differentiate infants with and without later ASD diagnoses in ways that are similar to later-born siblings of children with ASD. Repetitive behaviors and cognitive and adaptive impairments are present in all FXS infants throughout development, suggesting that these deficits reflect the general FXS phenotype and not ASD in FXS specifically. PMID:28281129

Delineation of behavioral phenotypes in genetic syndromes: characteristics of autism spectrum disorder, affect and hyperactivity.

PubMed

Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

2011-08-01

We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in CdLS and FXS. High levels of impulsivity were seen in SMS, AS, CdCS, FXS and adults with CdLS. Negative affect was prominent in adults with CdLS, while positive affect was prominent in adults with AS and FXS. Heightened levels of overactivity and impulsivity were identified in FXS, AS and SMS while low levels were identified in PWS. These findings confirm and extend previously reported behavioral phenotypes.

Anxiety, attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome.

PubMed

Wheeler, Anne; Raspa, Melissa; Bann, Carla; Bishop, Ellen; Hessl, David; Sacco, Pat; Bailey, Donald B

2014-01-01

Behavior problems are a common challenge for individuals with fragile X syndrome (FXS) and constitute the primary clinical outcome domain in trials testing new FXS medications. However, little is known about the relationship between caregiver-reported behavior problems and co-occurring conditions such as anxiety and attention problems. In this study, 350 caregivers, each with at least one son or daughter with full-mutation FXS, rated one of their children with FXS using the Aberrant Behavior Checklist-Community Version (ABC-C); the Anxiety subscale of the Anxiety, Depression, and Mood Scale; and the Attention/Hyperactivity Items from the Symptom Inventories. In addition to examining family consequences of these behaviors, this study also sought to replicate psychometric findings for the ABC-C in FXS, to provide greater confidence for its use in clinical trials with this population. Psychometric properties and baseline ratings of problem behavior were consistent with other recent studies, further establishing the profile of problem behavior in FXS. Cross-sectional analyses suggest that selected dimensions of problem behavior, anxiety, and hyperactivity are age related; thus, age should serve as an important control in any studies of problem behavior in FXS. Measures of anxiety, attention, and hyperactivity were highly associated with behavior problems, suggesting that these factors at least coincide with problem behavior. However, these problems generally did not add substantially to variance in caregiver burden predicted by elevated behavior problems. The results provide further evidence of the incidence of problem behaviors and co-occurring conditions in FXS and the impact of these behaviors on the family. © 2013 Wiley Periodicals, Inc.

Increasing our understanding of human cognition through the study of Fragile X Syndrome.

PubMed

Cook, Denise; Nuro, Erin; Murai, Keith K

2014-02-01

Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior. Copyright © 2013 Wiley Periodicals, Inc.

Visual Attention and Autistic Behavior in Infants with Fragile X Syndrome

ERIC Educational Resources Information Center

Roberts, Jane E.; Hatton, Deborah D.; Long, Anna C. J.; Anello, Vittoria; Colombo, John

2012-01-01

Aberrant attention is a core feature of fragile X syndrome (FXS), however, little is known regarding the developmental trajectory and underlying physiological processes of attention deficits in FXS. Atypical visual attention is an early emerging and robust indicator of autism in idiopathic (non-FXS) autism. Using a biobehavioral approach with gaze…

Autism in Fragile X Syndrome: A Category Mistake?

ERIC Educational Resources Information Center

Hall, Scott S.; Lightbody, Amy A.; Hirt, Melissa; Rezvani, Ava; Reiss, Allan L.

2010-01-01

Objective: Many investigators now routinely classify children with fragile X syndrome (FXS) according to whether or not they also meet diagnostic criteria for autism. To determine whether this classification is appropriate, we examined the profiles of autistic behaviors shown by boys and girls with FXS. Method: Individuals with FXS, aged 5 to 25…

Brief Report: Acamprosate in Fragile X Syndrome

ERIC Educational Resources Information Center

Erickson, Craig A.; Mullett, Jennifer E.; McDougle, Christopher J.

2010-01-01

Glutamatergic dysfunction is implicated in the pathophysiology of fragile X syndrome (FXS). We report on the first trial of acamprosate, a drug with putative mGluR5 antagonism, in three adults with FXS and autism. Medical records describing open-label treatment with acamprosate in 3 patients with FXS and a comorbid diagnosis of autistic disorder…

Pharmacogenetic Inhibition of eIF4E-Dependent Mmp9 mRNA Translation Reverses Fragile X Syndrome-like Phenotypes

PubMed Central

Gkogkas, Christos G.; Khoutorsky, Arkady; Cao, Ruifeng; Jafarnejad, Seyed Mehdi; Prager-Khoutorsky, Masha; Giannakas, Nikolaos; Kaminari, Archontia; Fragkouli, Apostolia; Nader, Karim; Price, Theodore J.; Konicek, Bruce W.; Graff, Jeremy R.; Tzinia, Athina K.; Lacaille, Jean-Claude; Sonenberg, Nahum

2015-01-01

SUMMARY Fragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS pheno-types. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1 −/y), we show that phosphorylation of the mRNA 5′ cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1 −/y mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS. PMID:25466251

The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells

PubMed Central

Zalfa, Francesca; Panasiti, Vincenzo; Carotti, Simone; Zingariello, Maria; Perrone, Giuseppe; Sancillo, Laura; Pacini, Laura; Luciani, Flavie; Roberti, Vincenzo; D'Amico, Silvia; Coppola, Rosa; Abate, Simona Osella; Rana, Rosa Alba; De Luca, Anastasia; Fiers, Mark; Melocchi, Valentina; Bianchi, Fabrizio; Farace, Maria Giulia; Achsel, Tilmann; Marine, Jean-Christophe; Morini, Sergio; Bagni, Claudia

2017-01-01

The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. FMRP affects metastasis formation in a mouse model for breast cancer. Here we show that FMRP is overexpressed in human melanoma with high Breslow thickness and high Clark level. Furthermore, meta-analysis of the TCGA melanoma data revealed that high levels of FMRP expression correlate significantly with metastatic tumor tissues, risk of relapsing and disease-free survival. Reduction of FMRP in metastatic melanoma cell lines impinges on cell migration, invasion and adhesion. Next-generation sequencing in human melanoma cells revealed that FMRP regulates a large number of mRNAs involved in relevant processes of melanoma progression. Our findings suggest an association between FMRP levels and the invasive phenotype in melanoma and might open new avenues towards the discovery of novel therapeutic targets. PMID:29144507

The fragile X mental retardation protein regulates tumor invasiveness-related pathways in melanoma cells.

PubMed

Zalfa, Francesca; Panasiti, Vincenzo; Carotti, Simone; Zingariello, Maria; Perrone, Giuseppe; Sancillo, Laura; Pacini, Laura; Luciani, Flavie; Roberti, Vincenzo; D'Amico, Silvia; Coppola, Rosa; Abate, Simona Osella; Rana, Rosa Alba; De Luca, Anastasia; Fiers, Mark; Melocchi, Valentina; Bianchi, Fabrizio; Farace, Maria Giulia; Achsel, Tilmann; Marine, Jean-Christophe; Morini, Sergio; Bagni, Claudia

2017-11-16

The fragile X mental retardation protein (FMRP) is lacking or mutated in patients with the fragile X syndrome (FXS), the most frequent form of inherited intellectual disability. FMRP affects metastasis formation in a mouse model for breast cancer. Here we show that FMRP is overexpressed in human melanoma with high Breslow thickness and high Clark level. Furthermore, meta-analysis of the TCGA melanoma data revealed that high levels of FMRP expression correlate significantly with metastatic tumor tissues, risk of relapsing and disease-free survival. Reduction of FMRP in metastatic melanoma cell lines impinges on cell migration, invasion and adhesion. Next-generation sequencing in human melanoma cells revealed that FMRP regulates a large number of mRNAs involved in relevant processes of melanoma progression. Our findings suggest an association between FMRP levels and the invasive phenotype in melanoma and might open new avenues towards the discovery of novel therapeutic targets.

Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links With Pragmatic Language

PubMed Central

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2014-01-01

This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 28 with typical development (TD), aged 4–15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did not differ from boys with ASD. Dampened vagal tone predicted pragmatic impairment in ASD, and associations emerged between cardiac activity and receptive/expressive vocabulary across groups. Findings support autonomic dysfunction as a mechanism underlying pragmatic impairment in ASD and suggest that biophysiological profiles are shared in ASD and FXS, which has implications for understanding the role of fragile X mental retardation-1 (FMR1, the FXS gene) in the pathophysiology of ASD. PMID:24432860

Working memory subsystems and task complexity in young boys with Fragile X syndrome.

PubMed

Baker, S; Hooper, S; Skinner, M; Hatton, D; Schaaf, J; Ornstein, P; Bailey, D

2011-01-01

Working memory problems have been targeted as core deficits in individuals with Fragile X syndrome (FXS); however, there have been few studies that have examined working memory in young boys with FXS, and even fewer studies that have studied the working memory performance of young boys with FXS across different degrees of complexity. The purpose of this study was to investigate the phonological loop and visual-spatial working memory in young boys with FXS, in comparison to mental age-matched typical boys, and to examine the impact of complexity of the working memory tasks on performance. The performance of young boys (7 to 13-years-old) with FXS (n = 40) was compared with that of mental age and race matched typically developing boys (n = 40) on measures designed to test the phonological loop and the visuospatial sketchpad across low, moderate and high degrees of complexity. Multivariate analyses were used to examine group differences across the specific working memory systems and degrees of complexity. Results suggested that boys with FXS showed deficits in phonological loop and visual-spatial working memory tasks when compared with typically developing mental age-matched boys. For the boys with FXS, the phonological loop was significantly lower than the visual-spatial sketchpad; however, there was no significant difference in performance across the low, moderate and high degrees of complexity in the working memory tasks. Reverse tasks from both the phonological loop and visual-spatial sketchpad appeared to be the most challenging for both groups, but particularly for the boys with FXS. These findings implicate a generalised deficit in working memory in young boys with FXS, with a specific disproportionate impairment in the phonological loop. Given the lack of differentiation on the low versus high complexity tasks, simple span tasks may provide an adequate estimate of working memory until greater involvement of the central executive is achieved. © 2010 The Authors. Journal of Intellectual Disability Research © 2010 Blackwell Publishing Ltd.

Working memory subsystems and task complexity in young boys with Fragile X syndrome

PubMed Central

Baker, S.; Hooper, S.; Skinner, M.; Hatton, D.; Schaaf, J.; Ornstein, P.; Bailey, D.

2011-01-01

Background Working memory problems have been targeted as core deficits in individuals with Fragile X syndrome (FXS); however, there have been few studies that have examined working memory in young boys with FXS, and even fewer studies that have studied the working memory performance of young boys with FXS across different degrees of complexity. The purpose of this study was to investigate the phonological loop and visual–spatial working memory in young boys with FXS, in comparison to mental age-matched typical boys, and to examine the impact of complexity of the working memory tasks on performance. Methods The performance of young boys (7 to 13-years-old) with FXS (n = 40) was compared with that of mental age and race matched typically developing boys (n = 40) on measures designed to test the phonological loop and the visuospatial sketchpad across low, moderate and high degrees of complexity. Multivariate analyses were used to examine group differences across the specific working memory systems and degrees of complexity. Results Results suggested that boys with FXS showed deficits in phonological loop and visual–spatial working memory tasks when compared with typically developing mental age-matched boys. For the boys with FXS, the phonological loop was significantly lower than the visual–spatial sketchpad; however, there was no significant difference in performance across the low, moderate and high degrees of complexity in the working memory tasks. Reverse tasks from both the phonological loop and visual–spatial sketchpad appeared to be the most challenging for both groups, but particularly for the boys with FXS. Conclusions These findings implicate a generalised deficit in working memory in young boys with FXS, with a specific disproportionate impairment in the phonological loop. Given the lack of differentiation on the low versus high complexity tasks, simple span tasks may provide an adequate estimate of working memory until greater involvement of the central executive is achieved. PMID:21121991

Tonotopic alterations in inhibitory input to the medial nucleus of the trapezoid body in a mouse model of Fragile X syndrome.

PubMed

McCullagh, Elizabeth A; Salcedo, Ernesto; Huntsman, Molly M; Klug, Achim

2017-11-01

Hyperexcitability and the imbalance of excitation/inhibition are one of the leading causes of abnormal sensory processing in Fragile X syndrome (FXS). The precise timing and distribution of excitation and inhibition is crucial for auditory processing at the level of the auditory brainstem, which is responsible for sound localization ability. Sound localization is one of the sensory abilities disrupted by loss of the Fragile X Mental Retardation 1 (Fmr1) gene. Using triple immunofluorescence staining we tested whether there were alterations in the number and size of presynaptic structures for the three primary neurotransmitters (glutamate, glycine, and GABA) in the auditory brainstem of Fmr1 knockout mice. We found decreases in either glycinergic or GABAergic inhibition to the medial nucleus of the trapezoid body (MNTB) specific to the tonotopic location within the nucleus. MNTB is one of the primary inhibitory nuclei in the auditory brainstem and participates in the sound localization process with fast and well-timed inhibition. Thus, a decrease in inhibitory afferents to MNTB neurons should lead to greater inhibitory output to the projections from this nucleus. In contrast, we did not see any other significant alterations in balance of excitation/inhibition in any of the other auditory brainstem nuclei measured, suggesting that the alterations observed in the MNTB are both nucleus and frequency specific. We furthermore show that glycinergic inhibition may be an important contributor to imbalances in excitation and inhibition in FXS and that the auditory brainstem is a useful circuit for testing these imbalances. © 2017 Wiley Periodicals, Inc.

Brief Report: Autism Symptoms in Infants with Fragile X Syndrome

ERIC Educational Resources Information Center

Roberts, Jane E.; Tonnsen, Bridgette L.; McCary, Lindsay M.; Caravella, Kelly E.; Shinkareva, Svetlana V.

2016-01-01

Fragile X syndrome (FXS) is the most common known genetic cause of autism spectrum disorder (ASD). Although 50-75% of children with FXS meet ASD criteria, no studies have compared ASD symptoms in infants with FXS versus other high risk groups, such as siblings of children with ASD (ASIBs). Using the Autism Observation Scale for Infants, our…

Auditory Brainstem Responses in Young Males with Fragile X Syndrome

ERIC Educational Resources Information Center

Roberts, Joanne; Hennon, Elizabeth A.; Anderson, Kathleen; Roush, Jackson; Gravel, Judith; Skinner, Martie; Misenheimer, Jan; Reitz, Patricia

2005-01-01

Fragile X syndrome (FXS) is the most common inherited cause of mental retardation resulting in developmental delays in males. Atypical outer ear morphology is characteristic of FXS and may serve as a marker for abnormal auditory function. Despite this abnormality, studies of the hearing of young males with FXS are generally lacking. A few studies…

Articulation Rate and Vowel Space Characteristics of Young Males with Fragile X Syndrome: Preliminary Acoustic Findings

ERIC Educational Resources Information Center

Zajac, David J.; Roberts, Joanne E.; Hennon, Elizabeth A.; Harris, Adrianne A.; Barnes, Elizabeth F.; Misenheimer, Jan

2006-01-01

Purpose: Increased speaking rate is a commonly reported perceptual characteristic among males with fragile X syndrome (FXS). The objective of this preliminary study was to determine articulation rate--one component of perceived speaking rate--and vowel space characteristics of young males with FXS. Method: Young males with FXS (n = 38), …

FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome

PubMed Central

Sherman, Stephanie L.; Kidd, Sharon A.; Riley, Catharine; Berry-Kravis, Elizabeth; Andrews, Howard F.; Miller, Robert M.; Lincoln, Sharyn; Swanson, Mark; Kaufmann, Walter E.; Brown, W. Ted

2017-01-01

BACKGROUND AND OBJECTIVE Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Through a collective effort, the Fragile X Clinic and Research Consortium developed the Fragile X Online Registry With Accessible Research Database (FORWARD) to facilitate multisite data collection. This report describes FORWARD and the way it can be used to improve health and quality of life of FXS patients and their relatives and caregivers. METHODS FORWARD collects demographic information on individuals with FXS and their family members (affected and unaffected) through a 1-time registry form. The longitudinal database collects clinician- and parent-reported data on individuals diagnosed with FXS, focused on those who are 0 to 24 years of age, although individuals of any age can participate. RESULTS The registry includes >2300 registrants (data collected September 7, 2009 to August 31, 2014). The longitudinal database includes data on 713 individuals diagnosed with FXS (data collected September 7, 2012 to August 31, 2014). Longitudinal data continue to be collected on enrolled patients along with baseline data on new patients. CONCLUSIONS FORWARD represents the largest resource of clinical and demographic data for the FXS population in the United States. These data can be used to advance our understanding of FXS: the impact of cooccurring conditions, the impact on the day-today lives of individuals living with FXS and their families, and short-term and long-term outcomes. PMID:28814539

FORWARD: A Registry and Longitudinal Clinical Database to Study Fragile X Syndrome.

PubMed

Sherman, Stephanie L; Kidd, Sharon A; Riley, Catharine; Berry-Kravis, Elizabeth; Andrews, Howard F; Miller, Robert M; Lincoln, Sharyn; Swanson, Mark; Kaufmann, Walter E; Brown, W Ted

2017-06-01

Advances in the care of patients with fragile X syndrome (FXS) have been hampered by lack of data. This deficiency has produced fragmentary knowledge regarding the natural history of this condition, healthcare needs, and the effects of the disease on caregivers. To remedy this deficiency, the Fragile X Clinic and Research Consortium was established to facilitate research. Through a collective effort, the Fragile X Clinic and Research Consortium developed the Fragile X Online Registry With Accessible Research Database (FORWARD) to facilitate multisite data collection. This report describes FORWARD and the way it can be used to improve health and quality of life of FXS patients and their relatives and caregivers. FORWARD collects demographic information on individuals with FXS and their family members (affected and unaffected) through a 1-time registry form. The longitudinal database collects clinician- and parent-reported data on individuals diagnosed with FXS, focused on those who are 0 to 24 years of age, although individuals of any age can participate. The registry includes >2300 registrants (data collected September 7, 2009 to August 31, 2014). The longitudinal database includes data on 713 individuals diagnosed with FXS (data collected September 7, 2012 to August 31, 2014). Longitudinal data continue to be collected on enrolled patients along with baseline data on new patients. FORWARD represents the largest resource of clinical and demographic data for the FXS population in the United States. These data can be used to advance our understanding of FXS: the impact of cooccurring conditions, the impact on the day-to-day lives of individuals living with FXS and their families, and short-term and long-term outcomes. Copyright © 2017 by the American Academy of Pediatrics.

Increasing our Understanding of Human Cognition Through the Study of Fragile X Syndrome

PubMed Central

Denise, Cook; Erin, Nuro; Keith, K. Murai

2014-01-01

Fragile X Syndrome (FXS) is considered the most common form of inherited intellectual disability. It is caused by reductions in the expression level or function of a single protein, the Fragile X Mental Retardation Protein (FMRP), a translational regulator which binds to approximately 4% of brain messenger RNAs. Accumulating evidence suggests that FXS is a complex disorder of cognition, involving interactions between genetic and environmental influences, leading to difficulties in acquiring key life skills including motor skills, language, and proper social behaviors. Since many FXS patients also present with one or more features of autism spectrum disorders (ASDs), insights gained from studying the monogenic basis of FXS could pave the way to a greater understanding of underlying features of multigenic ASDs. Here we present an overview of the FXS and FMRP field with the goal of demonstrating how loss of a single protein involved in translational control affects multiple stages of brain development and leads to debilitating consequences on human cognition. We also focus on studies which have rescued or improved FXS symptoms in mice using genetic or therapeutic approaches to reduce protein expression. We end with a brief description of how deficits in translational control are implicated in FXS and certain cases of ASDs, with many recent studies demonstrating that ASDs are likely caused by increases or decreases in the levels of certain key synaptic proteins. The study of FXS and its underlying single genetic cause offers an invaluable opportunity to study how a single gene influences brain development and behavior. © 2013 The Authors. Developmental Neurobiology Published by Wiley Periodicals, Inc. Develop Neurobiol 74: 147–177, 2014 PMID:23723176

Fragile X Mental Retardation Protein is Required for Programmed Cell Death and Clearance of Developmentally-Transient Peptidergic Neurons

PubMed Central

Gatto, Cheryl L.; Broadie, Kendal

2011-01-01

Fragile X syndrome (FXS), caused by loss of fragile X mental retardation 1 (FMR1) gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 product (FMRP) is an RNA-binding protein best established to function in activity-dependent modulation of synaptic connections. In the Drosophila FXS disease model, loss of functionally-conserved dFMRP causes synaptic overgrowth and overelaboration in pigment dispersing factor (PDF) peptidergic neurons in the adult brain. Here, we identify a very different component of PDF neuron misregulation in dfmr1 mutants: the aberrant retention of normally developmentally-transient PDF tritocerebral (PDF-TRI) neurons. In wild-type animals, PDF-TRI neurons in the central brain undergo programmed cell death and complete, processive clearance within days of eclosion. In the absence of dFMRP, a defective apoptotic program leads to constitutive maintenance of these peptidergic neurons. We tested whether this apoptotic defect is circuit-specific by examining crustacean cardioactive peptide (CCAP) and bursicon circuits, which are similarly developmentally-transient and normally eliminated immediately post-eclosion. In dfmr1 null mutants, CCAP/bursicon neurons also exhibit significantly delayed clearance dynamics, but are subsequently eliminated from the nervous system, in contrast to the fully persistent PDF-TRI neurons. Thus, the requirement of dFMRP for the retention of transitory peptidergic neurons shows evident circuit specificity. The novel defect of impaired apoptosis and aberrant neuron persistence in the Drosophila FXS model suggests an entirely new level of “pruning” dysfunction may contribute to the FXS disease state. PMID:21596027

Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome

PubMed Central

AlOlaby, Reem Rafik; Sweha, Stefan R; Silva, Marisol; Durbin-Johnson, Blythe; Yrigollen, Carolyn M; Pretto, Dalyir; Hagerman, Randi J; Tassone, Flora

2017-01-01

Objectives Several neurotransmitters involved in brain development are altered in fragile X syndrome (FXS), the most common monogenic cause of autism spectrum disorder (ASD). Serotonin plays a vital role in synaptogenesis and postnatal brain development. Deficits in serotonin synthesis and abnormal neurogenesis were shown in young children with autism, suggesting that treating within the first years of life with a selective serotonin reuptake inhibitor might be the most effective time. In this study we aimed to identify molecular biomarkers involved in the serotonergic pathway that could predict the response to sertraline treatment in young children with FXS. Methods Genotypes were determined for several genes involved in serotonergic pathway in 51 children with FXS, ages 24 to 68 months. Correlations between genotypes and deviations from baseline in primary and secondary outcome measures were modeled using linear regression models. Results A significant association was observed between a BDNF polymorphism and improvements for several clinical measures, including the Clinical Global Impression scale (P= 0.008) and the Cognitive T Score (P= 0.017) in those treated with sertraline compared to those in the placebo group. Additionally, polymorphisms in the MAOA, Cytochrome P450 2C19 and 2D6, and in the 5-HTTLPR gene showed a significant correlation with some of the secondary measures included in this study. Conclusion This study shows that polymorphisms of genes involved in the serotonergic pathway could play a potential role in predicting response to sertraline treatment in young children with FXS. Larger studies are warranted to confirm these initial findings. PMID:28242040

Working Memory Subsystems and Task Complexity in Young Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Baker, S.; Hooper, S.; Skinner, M.; Hatton, D.; Schaaf, J.; Ornstein, P.; Bailey, D.

2011-01-01

Background: Working memory problems have been targeted as core deficits in individuals with Fragile X syndrome (FXS); however, there have been few studies that have examined working memory in young boys with FXS, and even fewer studies that have studied the working memory performance of young boys with FXS across different degrees of complexity.…

Feasibility, Reproducibility, and Clinical Validity of the Pediatric Anxiety Rating Scale--Revised for Fragile X Syndrome

ERIC Educational Resources Information Center

Russo-Ponsaran, Nicole M.; Yesensky, Jessica; Hessl, David; Berry-Kravis Elizabeth

2014-01-01

Fragile X syndrome (FXS) is the most common inherited cause of intellectual disability and the most common known genetic cause of autism. FXS is associated with psychiatric impairments, including anxiety disorders. There is a paucity of well-developed measures to characterize anxiety in FXS. However, such scales are needed to measure therapeutic…

Reading and Phonological Skills in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Klusek, Jessica; Hunt, Anna W.; Mirrett, Penny L.; Hatton, Deborah D.; Hooper, Stephen R.; Roberts, Jane E.; Bailey, Donald B.

2015-01-01

Although reading skills are critical for the success of individuals with intellectual disabilities, literacy has received little attention in fragile X syndrome (FXS). This study examined the literacy profile of FXS. Boys with FXS (n = 51; mean age 10.2 years) and mental age-matched boys with typical development (n = 35) participated in…

Common and specific impairments in attention functioning in girls with chromosome 22q11.2 deletion, fragile X or Turner syndromes

PubMed Central

2014-01-01

Background Chromosome 22q11.2 deletion syndrome (22q11.2DS), fragile X syndrome (FXS), and Turner syndrome (TS) are complex and variable developmental syndromes caused by different genetic abnormalities; yet, they share similar cognitive impairments in the domains of numbers, space, and time. The atypical development of foundational neural networks that underpin the attentional system is thought to result in further impairments in higher-order cognitive functions. The current study investigates whether children with similar higher-order cognitive impairments but different genetic disorders also show similar impairments in alerting, orienting, and executive control of attention. Methods Girls with 22q11.2DS, FXS, or TS and typically developing (TD) girls, aged 7 to 15 years, completed an attention network test, a flanker task with alerting and orienting cues. Exploration of reaction times and accuracy allowed us to test for potential commonalities in attentional functioning in alerting, orienting, and executive control. Linear regression models were used to test whether the predictors of group and chronological age were able to predict differences in attention indices. Results Girls with 22q11.2DS, FXS, or TS demonstrated unimpaired function of the alerting system and impaired function of the executive control system. Diagnosis-specific impairments were found such that girls with FXS made more errors and had a reduced orienting index, while girls with 22q11.2DS showed specific age-related deficits in the executive control system. Conclusions These results suggest that the control but not the implementation of attention is selectively impaired in girls with 22q11.2DS, TS or FXS. Additionally, the age effect on executive control in girls with 22q11.2DS implies a possible altered developmental trajectory. PMID:24628892

Neurochemical evaluation of brain function with 1H magnetic resonance spectroscopy in patients with fragile X syndrome.

PubMed

Utine, G E; Akpınar, B; Arslan, U; Kiper, P Ö Ş; Volkan-Salancı, B; Alanay, Y; Aktaş, D; Haliloğlu, G; Oğuz, K K; Boduroğlu, K; Alikaşifoğlu, M

2014-01-01

Fragile X syndrome (FXS) is the most common hereditary disorder of intellectual disability. Cognitive deficits involve executive function, attention, learning and memory. Advanced neuroimaging techniques are available, and (1)H magnetic resonance spectroscopy (MRS) can be used as a complementary method to MR imaging to understand disease processes in brain, by in vivo demonstration of brain metabolites. MRS was performed in 13 male patients with FXS full mutation, and 13 age- and sex-matched healthy controls. FXS diagnosis was based on clinical evaluation, followed by detection of FMR1 full mutation. Axial T2 TSE, sagittal T1 SE and coronal 3D MPRAGE images were obtained for both morphological imaging and voxel localization. Following evaluation of conventional images, multivoxel MRS (CSI) through supraventricular white matter and single voxel MRS (svs) with an intermediate echo time (TE:135 ms) from the cerebellar vermis were performed. Choline/Creatine (Cho/Cr), N-acetyl aspartate/Creatine (NAA/Cr), and Choline/N-acetyl aspartate (Cho/NAA) ratios were examined at right frontal (RF), left frontal (LF), right parietal (RP), left parietal (LP), and cerebellar vermian (C) white matter. Statistical analyses were done using t-test and Mann-Whitney U tests. A statistically significant difference was observed in RP Cho/NAA ratio (cell membrane marker/neuroaxonal marker), FXS patients having lower levels than controls (P = 0.016). The results should be evaluated cautiously in parallel to consequences in brain metabolism leading to alterations in neurotransmitter levels, osmoregulation, energy metabolism and oxidative stress response described in animal models. MRS may serve to define a metabolic signature and biomarkers associated with FXS. © 2013 Wiley Periodicals, Inc.

Autism Spectrum Disorder (ASD) and Fragile X Syndrome (FXS): Two Overlapping Disorders Reviewed through Electroencephalography—What Can be Interpreted from the Available Information?

PubMed Central

Mc Devitt, Niamh; Gallagher, Louise; Reilly, Richard B.

2015-01-01

Autism Spectrum Disorder (ASD) and Fragile X syndrome (FXS) are neurodevelopmental disorders with different but potentially related neurobiological underpinnings, which exhibit significant overlap in their behavioural symptoms. FXS is a neurogenetic disorder of known cause whereas ASD is a complex genetic disorder, with both rare and common genetic risk factors and likely genetic and environmental interaction effects. A comparison of the phenotypic presentation of the two disorders may highlight those symptoms that are more likely to be under direct genetic control, for example in FXS as opposed to shared symptoms that are likely to be under the control of multiple mechanisms. This review is focused on the application and analysis of electroencephalography data (EEG) in ASD and FXS. Specifically, Event Related Potentials (ERP) and resting state studies (rEEG) studies investigating ASD and FXS cohorts are compared. This review explores the electrophysiological similarities and differences between the two disorders in addition to the potentially associated neurobiological mechanisms at play. A series of pertinent research questions which are suggested in the literature are also posed within the review. PMID:25826237

Narrative Skill in Boys with Fragile X Syndrome with and without Autism Spectrum Disorder

PubMed Central

Estigarribia, Bruno; Martin, Gary E.; Roberts, Joanne E.; Spencer, Amy; Gucwa, Agnieszka; Sideris, John

2010-01-01

We examined recalled narratives of boys with fragile X syndrome with autism spectrum disorder (FXS-ASD; N=28) and without ASD (FXS-O; N=29), and compared them to those of boys with Down syndrome (DS; N=33) and typically developing boys (TD; N=39). Narratives were scored for mentions of macrostructural Story Grammar elements (Introduction, Relationship, Initiating Events, Internal Response, Attempts/Actions, and Ending). We found that narrative recall is predicted by short-term memory and nonverbal mental age levels in almost all groups (except TD), but not by expressive syntax or caregiver education. After adjusting for these covariates, there were no differences between the three groups with intellectual disability (ID). The FXS-ASD group, however, had significantly poorer performance than the TD group on the overall Story Grammar score, and both the FXS-O and FXS-ASD groups had lower Attempts/Actions scores than the TD group. We conclude that some form of narrative impairment may be associated with FXS, that this impairment may be shared by other forms of ID, and that the presence of ASD has a significantly detrimental effect on narrative recall. PMID:21516264

Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes.

PubMed

Gkogkas, Christos G; Khoutorsky, Arkady; Cao, Ruifeng; Jafarnejad, Seyed Mehdi; Prager-Khoutorsky, Masha; Giannakas, Nikolaos; Kaminari, Archontia; Fragkouli, Apostolia; Nader, Karim; Price, Theodore J; Konicek, Bruce W; Graff, Jeremy R; Tzinia, Athina K; Lacaille, Jean-Claude; Sonenberg, Nahum

2014-12-11

Fragile X syndrome (FXS) is the leading genetic cause of autism. Mutations in Fmr1 (fragile X mental retardation 1 gene) engender exaggerated translation resulting in dendritic spine dysmorphogenesis, synaptic plasticity alterations, and behavioral deficits in mice, which are reminiscent of FXS phenotypes. Using postmortem brains from FXS patients and Fmr1 knockout mice (Fmr1(-/y)), we show that phosphorylation of the mRNA 5' cap binding protein, eukaryotic initiation factor 4E (eIF4E), is elevated concomitant with increased expression of matrix metalloproteinase 9 (MMP-9) protein. Genetic or pharmacological reduction of eIF4E phosphorylation rescued core behavioral deficits, synaptic plasticity alterations, and dendritic spine morphology defects via reducing exaggerated translation of Mmp9 mRNA in Fmr1(-/y) mice, whereas MMP-9 overexpression produced several FXS-like phenotypes. These results uncover a mechanism of regulation of synaptic function by translational control of Mmp-9 in FXS, which opens the possibility of new treatment avenues for the diverse neurological and psychiatric aspects of FXS. Copyright © 2014 The Authors. Published by Elsevier Inc. All rights reserved.

Employment impact and financial burden for families of children with fragile X syndrome: findings from the National Fragile X Survey.

PubMed

Ouyang, L; Grosse, S; Raspa, M; Bailey, D

2010-10-01

The employment impact and financial burden experienced by families of children with fragile X syndrome (FXS) has not been quantified in the USA. Using a national fragile X family survey, we analysed data on 1019 families with at least one child who had a full FXS mutation. Out-of-pocket expenditures related to fragile X were reported. We used logistic regression to examine the role of insurance, number of affected children, and number of total co-occurring conditions in predicting the financial burden and employment impact of FXS, while adjusting for race, education, marital status and other sociodemographic predictors. Almost half of families affected by FXS reported that they had experienced an increased financial burden and nearly 60% stated that they had had to change work hours or stop work because of FXS. Families with health insurance that met family needs were significantly less likely to report an excess financial burden. The type of insurance (private or public) was not associated with the reported financial burden. Affected children's mutation status, especially male children with the full mutation, was associated with employment impact. The total number of co-occurring conditions was associated with both financial burden and employment impact. Families affected by FXS experienced a significant employment impact and financial burden. Policies designed to help families with FXS need to take into consideration the dimension of co-occurring conditions. © 2010 The Authors. Journal of Intellectual Disability Research © 2010 Blackwell Publishing Ltd.

Longitudinal Profiles of Expressive Vocabulary, Syntax and Pragmatic Language in Boys with Fragile X Syndrome or Down Syndrome

ERIC Educational Resources Information Center

Martin, Gary E.; Losh, Molly; Estigarribia, Bruno; Sideris, John; Roberts, Joanne

2013-01-01

Background: Fragile X syndrome (FXS) and Down syndrome (DS) are the two leading genetic causes of intellectual disability, and FXS is the most common known genetic condition associated with autism. Both FXS and DS are associated with significant language impairment, but little is known about expressive language across domains over time or the role…

Down Syndrome and Fragile X Syndrome in a Colombian Woman: Case Report

ERIC Educational Resources Information Center

Saldarriaga, Wilmar; Ruiz, Fabian Andres; Tassone, Flora; Hagerman, Randi

2017-01-01

Background: Down syndrome (DS) and Fragile X syndrome (FXS) are the major genetic causes of intellectual disabilities. Here, we present a case of a 32-year-old woman with the diagnosis of both FXS and DS. She is the daughter of a 47-year-old pre-mutation woman who also has three sons with FXS. Methods: Cytogenetic testing detected the presence of…

Physiological Arousal in Autism and Fragile X Syndrome: Group Comparisons and Links with Pragmatic Language

ERIC Educational Resources Information Center

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2013-01-01

This study tested the hypothesis that pragmatic (i.e., social) language impairment is linked to arousal dysregulation in autism spectrum disorder (ASD) and fragile X syndrome (FXS). Forty boys with ASD, 39 with FXS, and 27 with typical development (TD), aged 4-15 years, participated. Boys with FXS were hyperaroused compared to boys with TD but did…

Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics

PubMed Central

Bagni, Claudia; Tassone, Flora; Neri, Giovanni; Hagerman, Randi

2012-01-01

Fragile X syndrome (FXS) is the most frequent form of inherited intellectual disability and is also linked to other neurologic and psychiatric disorders. FXS is caused by a triplet expansion that inhibits expression of the FMR1 gene; the gene product, FMRP, regulates mRNA metabolism in the brain and thus controls the expression of key molecules involved in receptor signaling and spine morphology. While there is no definitive cure for FXS, the understanding of FMRP function has paved the way for rational treatment designs that could potentially reverse many of the neurobiological changes observed in FXS. Additionally, behavioral, pharmacological, and cognitive interventions can raise the quality of life for both patients and their families. PMID:23202739

The Prader-Willi phenotype of fragile X syndrome.

PubMed

Nowicki, Stephen T; Tassone, Flora; Ono, Michele Y; Ferranti, Jessica; Croquette, Marie Francoise; Goodlin-Jones, Beth; Hagerman, Randi J

2007-04-01

The Prader-Willi phenotype (PWP) of fragile X syndrome (FXS) is associated with obesity and hyperphagia similar to Prader-Willi syndrome (PWS), but without cytogenetic or methylation abnormalities at 15q11-13. Thirteen cases of PWP and FXS are reported here that were identified by obesity and hyperphagia. Delayed puberty was seen in 5 of 9 cases who had entered puberty, a small penis or testicles in seven of 13 cases, and infant hypotonia and/or a poor suck in seven of 13 cases. Autism spectrum disorder occurred in 10 of 13 cases, and autism was diagnosed in seven of 13 cases. We investigated cytoplasmic interacting FMR1 protein (CYFIP) expression, which is a protein that interacts with FMR1 protein (FMRP) because the gene for CYFIP is located at 15q11-13. CYFIP mRNA levels were significantly reduced in our patients with the PWP and FXS compared to individuals without FXS (p < .001) and also individuals with FXS without PWP (p = .03).

Language comprehension profiles of young adolescents with fragile X syndrome.

PubMed

Oakes, Ashley; Kover, Sara T; Abbeduto, Leonard

2013-11-01

In this study, the authors sought to characterize the language phenotype of fragile X syndrome (FXS), focusing on the extent of impairment in receptive syntax, within-syndrome variability in those impairments in relation to gender, and the syndrome specificity of those impairments. The Test for Reception of Grammar, Version 2 ( Bishop, 2003), was used to examine the overall receptive syntactic skills of adolescents with FXS ( n = 35; 30 males, 5 females), adolescents with Down syndrome (DS; n = 28; 18 males, 10 females), and younger typically developing (TD) children ( n = 23; 14 males, 9 females) matched on nonverbal cognition. Performance on specific grammatical constructions and error types was examined for a subset of matched participants. Participants with FXS had overall receptive syntax scores that were lower than those of the TD participants but higher than those of the participants with DS; however, there was no difference in performance between the FXS and DS groups when females were excluded. Grammatical constructions that were especially difficult for participants with FXS and those with DS were identified, especially relative clause constructions and reversible constructions requiring attention to word order encoded by syntactic features. The current findings have implications for understanding the nature of the language learning difficulties of individuals with FXS and for language interventions.

Fragile X Syndrome

PubMed Central

Tassone, Flora; González-Teshima, Laura Yuriko; Forero-Forero, Jose Vicente; Ayala-Zapata, Sebastián; Hagerman, Randi

2014-01-01

Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation. Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children. PMID:25767309

Chronic minocycline treatment improves hippocampal neuronal structure, NMDA receptor function, and memory processing in Fmr1 knockout mice.

PubMed

Yau, S Y; Bettio, Luis; Vetrici, M; Truesdell, A; Chiu, C; Chiu, J; Truesdell, E; Christie, B R

2018-05-01

Fragile X Syndrome (FXS) is the most common inherited cause of intellectual disability, and is the leading known single-gene cause of autism spectrum disorder. FXS patients display varied behavioural deficits that include mild to severe cognitive impairments in addition to mood disorders. Currently there is no cure for this condition, however minocycline is becoming commonly prescribed as a treatment for FXS patients. Minocycline has been reported to alleviate social behavioural deficits, and improve verbal functioning in patients with FXS; however, its mode of action is not well understood. Previously we have shown that FXS results in learning impairments that involve deficits in N-methyl-d-aspartate (NMDA) receptor-dependent synaptic plasticity in the hippocampal dentate gyrus (DG). Here we tested whether chronic treatment with minocycline can improve these deficits by enhancing NMDA receptor-dependent functional and structural plasticity in the DG. Minocycline treatment resulted in a significant enhancement in NMDA receptor function in the dentate granule cells. This was accompanied by an increase in PSD-95 and GluN2A and GluN2B subunits in hippocampal synaptoneurosome fractions. Minocycline treatment also enhanced dentate granule cell dendritic length and branching. In addition, our results show that chronic minocycline treatment can rescue performance in novel object recognition in FXS mice. These findings indicate that minocycline treatment has both structural and functional benefits for hippocampal cells, which may partly contribute to the pro-cognitive effects minocycline appears to have for treating FXS. Copyright © 2018 Elsevier Inc. All rights reserved.

Development of a fragile X syndrome (FXS) knowledge scale: towards a modified multidimensional measure of informed choice for FXS population carrier screening.

PubMed

Ames, Alice G; Jaques, Alice; Ukoumunne, Obioha C; Archibald, Alison D; Duncan, Rony E; Emery, Jon; Metcalfe, Sylvia A

2015-02-01

Genetic carrier screening is increasingly possible for many conditions, but it is important to ensure decisions are informed. The multidimensional measure of informed choice (MMIC) is a quantitative instrument developed to evaluate informed choice in prenatal screening for Down syndrome, measuring knowledge, attitudes and uptake. To apply the MMIC in other screening settings, the knowledge scale must be modified. To develop and validate a modified MMIC knowledge scale for use with women undergoing carrier screening for fragile X syndrome (FXS). Responses to MMIC items were collected through questionnaires as part of a FXS carrier screening pilot study in a preconception setting in Melbourne, Australia. Ten knowledge scale items were developed using a modified Delphi technique. Cronbach's alpha and factor analysis were used to validate the new FXS knowledge scale. We summarized the knowledge, attitudes and informed choice status based on the modified MMIC. Two hundred and eighty-five women were recruited, 241 eligible questionnaires were complete for analysis. The FXS knowledge scale items measured one salient construct and were internally consistent (alpha = 0.70). 71% (172/241) of participants were classified as having good knowledge, 70% (169/241) had positive attitudes and 27% (65/241) made an informed choice to accept or decline screening. We present the development of a knowledge scale as part of a MMIC to evaluate informed choice in population carrier screening for FXS. This can be used as a template by other researchers to develop knowledge scales for other conditions for use in the MMIC. © 2012 John Wiley & Sons Ltd.

Social Communication and Theory of Mind in Boys with Autism and Fragile X Syndrome

PubMed Central

Losh, Molly; Martin, Gary E.; Klusek, Jessica; Hogan-Brown, Abigail L.; Sideris, John

2012-01-01

Impairments in the social use of language, or pragmatics, constitute a core characteristic of autism. Problems with pragmatic language have also been documented in fragile X syndrome (FXS), a monogenic condition that is the most common known genetic cause of autism. Evidence suggests that social cognitive ability, or theory of mind, may also be impaired in both conditions, and in autism, may importantly relate to pragmatic language ability. Given the substantial overlap observed in autism and FXS, this study aimed to better define those social-communicative phenotypes that overlap in these two conditions by comparing pragmatic language ability and theory of mind in children with idiopathic autism and children with FXS, with and without autism, as well as children with Down syndrome and typically developing controls. We further examined correlations between these cognitive-behavioral phenotypes and molecular genetic variation related to the Fragile X Mental Retardation-1 gene (FMR1) in the FXS group. Results indicated that children with idiopathic autism and those with FXS and autism performed comparably on direct-assessment measures of pragmatic language and theory of mind, whereas those with FXS only did not differ from controls. Theory of mind was related to pragmatic language ability in all groups. Pragmatic language and theory of mind also correlated with genetic variation at the FMR1 locus (Cytosine-Guanine-Guanine repeats and percent methylation). These results point toward substantial overlap in the social and language phenotypes in autism and FXS and suggest a molecular genetic basis to these phenotypic profiles. PMID:22934085

Social communication and theory of mind in boys with autism and fragile x syndrome.

PubMed

Losh, Molly; Martin, Gary E; Klusek, Jessica; Hogan-Brown, Abigail L; Sideris, John

2012-01-01

Impairments in the social use of language, or pragmatics, constitute a core characteristic of autism. Problems with pragmatic language have also been documented in fragile X syndrome (FXS), a monogenic condition that is the most common known genetic cause of autism. Evidence suggests that social cognitive ability, or theory of mind, may also be impaired in both conditions, and in autism, may importantly relate to pragmatic language ability. Given the substantial overlap observed in autism and FXS, this study aimed to better define those social-communicative phenotypes that overlap in these two conditions by comparing pragmatic language ability and theory of mind in children with idiopathic autism and children with FXS, with and without autism, as well as children with Down syndrome and typically developing controls. We further examined correlations between these cognitive-behavioral phenotypes and molecular genetic variation related to the Fragile X Mental Retardation-1 gene (FMR1) in the FXS group. Results indicated that children with idiopathic autism and those with FXS and autism performed comparably on direct-assessment measures of pragmatic language and theory of mind, whereas those with FXS only did not differ from controls. Theory of mind was related to pragmatic language ability in all groups. Pragmatic language and theory of mind also correlated with genetic variation at the FMR1 locus (Cytosine-Guanine-Guanine repeats and percent methylation). These results point toward substantial overlap in the social and language phenotypes in autism and FXS and suggest a molecular genetic basis to these phenotypic profiles.

Molecular biomarkers predictive of sertraline treatment response in young children with fragile X syndrome.

PubMed

AlOlaby, Reem Rafik; Sweha, Stefan R; Silva, Marisol; Durbin-Johnson, Blythe; Yrigollen, Carolyn M; Pretto, Dalyir; Hagerman, Randi J; Tassone, Flora

2017-06-01

Several neurotransmitters involved in brain development are altered in fragile X syndrome (FXS), the most common monogenic cause of autism spectrum disorder (ASD). Serotonin plays a vital role in synaptogenesis and postnatal brain development. Deficits in serotonin synthesis and abnormal neurogenesis were shown in young children with autism, suggesting that treating within the first years of life with a selective serotonin reuptake inhibitor might be the most effective time. In this study we aimed to identify molecular biomarkers involved in the serotonergic pathway that could predict the response to sertraline treatment in young children with FXS. Genotypes were determined for several genes involved in serotonergic pathway in 51 children with FXS, ages 24-72months. Correlations between genotypes and deviations from baseline in primary and secondary outcome measures were modeled using linear regression models. A significant association was observed between a BDNF polymorphism and improvements for several clinical measures, including the Clinical Global Impression scale (P=0.008) and the cognitive T score (P=0.017) in those treated with sertraline compared to those in the placebo group. Additionally, polymorphisms in the MAOA, Cytochrome P450 2C19 and 2D6, and in the 5-HTTLPR gene showed a significant correlation with some of the secondary measures included in this study. This study shows that polymorphisms of genes involved in the serotonergic pathway could play a potential role in predicting response to sertraline treatment in young children with FXS. Larger studies are warranted to confirm these initial findings. Copyright © 2017 The Japanese Society of Child Neurology. Published by Elsevier B.V. All rights reserved.

GABAergic circuit dysfunction in the Drosophila Fragile X syndrome model.

PubMed

Gatto, Cheryl L; Pereira, Daniel; Broadie, Kendal

2014-05-01

Fragile X syndrome (FXS), caused by loss of FMR1 gene function, is the most common heritable cause of intellectual disability and autism spectrum disorders. The FMR1 protein (FMRP) translational regulator mediates activity-dependent control of synapses. In addition to the metabotropic glutamate receptor (mGluR) hyperexcitation FXS theory, the GABA theory postulates that hypoinhibition is causative for disease state symptoms. Here, we use the Drosophila FXS model to assay central brain GABAergic circuitry, especially within the Mushroom Body (MB) learning center. All 3 GABAA receptor (GABAAR) subunits are reportedly downregulated in dfmr1 null brains. We demonstrate parallel downregulation of glutamic acid decarboxylase (GAD), the rate-limiting GABA synthesis enzyme, although GABAergic cell numbers appear unaffected. Mosaic analysis with a repressible cell marker (MARCM) single-cell clonal studies show that dfmr1 null GABAergic neurons innervating the MB calyx display altered architectural development, with early underdevelopment followed by later overelaboration. In addition, a new class of extra-calyx terminating GABAergic neurons is shown to include MB intrinsic α/β Kenyon Cells (KCs), revealing a novel level of MB inhibitory regulation. Functionally, dfmr1 null GABAergic neurons exhibit elevated calcium signaling and altered kinetics in response to acute depolarization. To test the role of these GABAergic changes, we attempted to pharmacologically restore GABAergic signaling and assay effects on the compromised MB-dependent olfactory learning in dfmr1 mutants, but found no improvement. Our results show that GABAergic circuit structure and function are impaired in the FXS disease state, but that correction of hypoinhibition alone is not sufficient to rescue a behavioral learning impairment. Copyright © 2014 Elsevier Inc. All rights reserved.

Reading in Children With Fragile X Syndrome: Phonological Awareness and Feasibility of Intervention.

PubMed

Adlof, Suzanne M; Klusek, Jessica; Hoffmann, Anne; Chitwood, Kerrie L; Brazendale, Allison; Riley, Karen; Abbeduto, Leonard J; Roberts, Jane E

2018-05-01

Individuals with fragile X syndrome (FXS) present with significant deficits in reading skills, but scant research exists to understand the characteristics of the reading delays or best practices for reading instruction with this population. Study 1 examined the relationship between phonological awareness and reading skills in individuals with FXS. Study 2 evaluated the feasibility of a web-based reading intervention, which incorporated phonological awareness and phonics instruction but was originally developed for mainstream students, for children with FXS. Results suggest that phonological awareness and reading skills are correlated in this population, and that instruction targeting phonological awareness and phonics should not be ruled out for individuals with FXS. Further studies are needed to examine their potential effects.

CGG-repeat dynamics and FMR1 gene silencing in fragile X syndrome stem cells and stem cell-derived neurons.

PubMed

Zhou, Yifan; Kumari, Daman; Sciascia, Nicholas; Usdin, Karen

2016-01-01

Fragile X syndrome (FXS), a common cause of intellectual disability and autism, results from the expansion of a CGG-repeat tract in the 5' untranslated region of the FMR1 gene to >200 repeats. Such expanded alleles, known as full mutation (FM) alleles, are epigenetically silenced in differentiated cells thus resulting in the loss of FMRP, a protein important for learning and memory. The timing of repeat expansion and FMR1 gene silencing is controversial. We monitored the repeat size and methylation status of FMR1 alleles with expanded CGG repeats in patient-derived induced pluripotent stem cells (iPSCs) and embryonic stem cells (ESCs) that were grown for extended period of time either as stem cells or differentiated into neurons. We used a PCR assay optimized for the amplification of large CGG repeats for sizing, and a quantitative methylation-specific PCR for the analysis of FMR1 promoter methylation. The FMR1 mRNA levels were analyzed by qRT-PCR. FMRP levels were determined by western blotting and immunofluorescence. Chromatin immunoprecipitation was used to study the association of repressive histone marks with the FMR1 gene in FXS ESCs. We show here that while FMR1 gene silencing can be seen in FXS embryonic stem cells (ESCs), some silenced alleles contract and when the repeat number drops below ~400, DNA methylation erodes, even when the repeat number remains >200. The resultant active alleles do not show the large step-wise expansions seen in stem cells from other repeat expansion diseases. Furthermore, there may be selection against large active alleles and these alleles do not expand further or become silenced on neuronal differentiation. Our data support the hypotheses that (i) large expansions occur prezygotically or in the very early embryo, (ii) large unmethylated alleles may be deleterious in stem cells, (iii) methylation can occur on alleles with >400 repeats very early in embryogenesis, and (iv) expansion and contraction may occur by different mechanisms. Our data also suggest that the threshold for stable methylation of FM alleles may be higher than previously thought. A higher threshold might explain why some carriers of FM alleles escape methylation. It may also provide a simple explanation for why silencing has not been observed in mouse models with >200 repeats.

Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model.

PubMed

Monyak, R E; Emerson, D; Schoenfeld, B P; Zheng, X; Chambers, D B; Rosenfelt, C; Langer, S; Hinchey, P; Choi, C H; McDonald, T V; Bolduc, F V; Sehgal, A; McBride, S M J; Jongens, T A

2017-08-01

Fragile X syndrome (FXS) is an undertreated neurodevelopmental disorder characterized by low intelligence quotent and a wide range of other symptoms including disordered sleep and autism. Although FXS is the most prevalent inherited cause of intellectual disability, its mechanistic underpinnings are not well understood. Using Drosophila as a model of FXS, we showed that select expression of dfmr1 in the insulin-producing cells (IPCs) of the brain was sufficient to restore normal circadian behavior and to rescue the memory deficits in the fragile X mutant fly. Examination of the insulin signaling (IS) pathway revealed elevated levels of Drosophila insulin-like peptide 2 (Dilp2) in the IPCs and elevated IS in the dfmr1 mutant brain. Consistent with a causal role for elevated IS in dfmr1 mutant phenotypes, the expression of dfmr1 specifically in the IPCs reduced IS, and genetic reduction of the insulin pathway also led to amelioration of circadian and memory defects. Furthermore, we showed that treatment with the FDA-approved drug metformin also rescued memory. Finally, we showed that reduction of IS is required at different time points to rescue circadian behavior and memory. Our results indicate that insulin misregulation underlies the circadian and cognitive phenotypes displayed by the Drosophila fragile X model, and thus reveal a metabolic pathway that can be targeted by new and already approved drugs to treat fragile X patients.

Neuropathologic features in the hippocampus and cerebellum of three older men with fragile X syndrome

PubMed Central

2011-01-01

Background Fragile X syndrome (FXS) is the most common inherited form of intellectual disability, and is the most common single-gene disorder known to be associated with autism. Despite recent advances in functional neuroimaging and our understanding of the molecular pathogenesis, only limited neuropathologic information on FXS is available. Methods Neuropathologic examinations were performed on post-mortem brain tissue from three older men (aged 57, 64 and 78 years) who had received a clinical or genetic diagnosis of FXS. In each case, physical and cognitive features were typical of FXS, and one man was also diagnosed with autism. Guided by reports of clinical and neuroimaging abnormalities of the limbic system and cerebellum of individuals with FXS, the current analysis focused on neuropathologic features present in the hippocampus and the cerebellar vermis. Results Histologic and immunologic staining revealed abnormalities in both the hippocampus and cerebellar vermis. Focal thickening of hippocampal CA1 and irregularities in the appearance of the dentate gyrus were identified. All lobules of the cerebellar vermis and the lateral cortex of the posterior lobe of the cerebellum had decreased numbers of Purkinje cells, which were occasionally misplaced, and often lacked proper orientation. There were mild, albeit excessive, undulations of the internal granular cell layer, with patchy foliar white matter axonal and astrocytic abnormalities. Quantitative analysis documented panfoliar atrophy of both the anterior and posterior lobes of the vermis, with preferential atrophy of the posterior lobule (VI to VII) compared with age-matched normal controls. Conclusions Significant morphologic changes in the hippocampus and cerebellum in three adult men with FXS were identified. This pattern of pathologic features supports the idea that primary defects in neuronal migration, neurogenesis and aging may underlie the neuropathology reported in FXS. PMID:21303513

Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice.

PubMed

Westmark, Cara J; Westmark, Pamela R; O'Riordan, Kenneth J; Ray, Brian C; Hervey, Crystal M; Salamat, M Shahriar; Abozeid, Sara H; Stein, Kelsey M; Stodola, Levi A; Tranfaglia, Michael; Burger, Corinna; Berry-Kravis, Elizabeth M; Malter, James S

2011-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading known genetic cause of autism. Fragile X mental retardation protein (FMRP), which is absent or expressed at substantially reduced levels in FXS, binds to and controls the postsynaptic translation of amyloid β-protein precursor (AβPP) mRNA. Cleavage of AβPP can produce β-amyloid (Aβ), a 39-43 amino acid peptide mis-expressed in Alzheimer's disease (AD) and Down syndrome (DS). Aβ is over-expressed in the brain of Fmr1(KO) mice, suggesting a pathogenic role in FXS. To determine if genetic reduction of AβPP/Aβ rescues characteristic FXS phenotypes, we assessed audiogenic seizures (AGS), anxiety, the ratio of mature versus immature dendritic spines and metabotropic glutamate receptor (mGluR)-mediated long-term depression (LTD) in Fmr1(KO) mice after removal of one App allele. All of these phenotypes were partially or completely reverted to normal. Plasma Aβ(1-42) was significantly reduced in full-mutation FXS males compared to age-matched controls while cortical and hippocampal levels were somewhat increased, suggesting that Aβ is sequestered in the brain. Evolving therapies directed at reducing Aβ in AD may be applicable to FXS and Aβ may serve as a plasma-based biomarker to facilitate disease diagnosis or assess therapeutic efficacy.

The role of ionotropic glutamate receptors in childhood neurodevelopmental disorders: autism spectrum disorders and fragile x syndrome.

PubMed

Uzunova, Genoveva; Hollander, Eric; Shepherd, Jason

2014-01-01

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.

Stranger Fear and Early Risk for Social Anxiety in Preschoolers with Fragile X Syndrome Contrasted to Autism Spectrum Disorder.

PubMed

Scherr, Jessica F; Hogan, Abigail L; Hatton, Deborah; Roberts, Jane E

2017-12-01

This study investigated behavioral indicators of social fear in preschool boys with fragile X syndrome (FXS) with a low degree of autism spectrum disorder (ASD) symptoms (FXS-Low; n = 29), FXS with elevated ASD symptoms (FXS-High; n = 25), idiopathic ASD (iASD; n = 11), and typical development (TD; n = 36). Gaze avoidance, escape behaviors, and facial fear during a stranger approach were coded. Boys with elevated ASD symptoms displayed more avoidant gaze, looking less at the stranger and parent than those with low ASD symptoms across etiologies. The iASD group displayed more facial fear than the other groups. Results suggest etiologically distinct behavioral patterns of social fear in preschoolers with elevated ASD symptoms.

Dietary milled flaxseed and flaxseed oil improve N-3 fatty acid status and do not affect glycemic control in individuals with well-controlled type 2 diabetes.

PubMed

Taylor, Carla G; Noto, Amy D; Stringer, Danielle M; Froese, Sylvia; Malcolmson, Linda

2010-02-01

To determine the effects of dietary consumption of milled flaxseed or flaxseed oil on glycemic control, n-3 fatty acid status, anthropometrics, and adipokines in individuals with type 2 diabetes. Thirty-four participants were randomized into a parallel, controlled trial. The participants were adults with type 2 diabetes (age 52.4 +/- 1.5 years, body mass index 32.4 +/- 1.0 kg/m(2), n = 17 men and 17 women). Participants consumed a selection of bakery products containing no flax (control group [CTL], n = 9), milled flaxseed (FXS, n = 13; 32 g/d), or flaxseed oil (FXO, n = 12; 13 g/d) daily for 12 weeks. The FXS and FXO groups received equivalent amounts of alpha-linolenic acid (ALA; 7.4 g/day). The primary outcome measures were fasting plasma hemoglobin A(1c), glucose, insulin, and phospholipid fatty acid composition. The secondary outcome measures were fasting circulating leptin and adiponectin, as well as body weight, body mass index, and waist circumference. Dietary intake assessment and calculations for homeostasis model assessment for insulin resistance and quantified insulin sensitivity check were also completed. The FXS and FXO groups had increases in plasma phospholipid n-3 fatty acids (ALA, eicosapentaenoic acid [EPA], or decosapentaenoic acid [DPA], but not docosahexaenoic acid), and the FXO group had more EPA and DPA in plasma phospholipids compared to the FXS group. All groups had similar caloric intakes; however, the CTL group experienced a 4% weight gain compared to baseline (p < 0.05), while both flax groups had constant body weights during the study period. All other parameters, including glycemic control, were unchanged by dietary treatment. Milled FXS and FXO intake does not affect glycemic control in adults with well-controlled type 2 diabetes. Possible prevention of weight gain by flax consumption warrants further investigation.

Mavoglurant in fragile X syndrome: Results of two randomized, double-blind, placebo-controlled trials.

PubMed

Berry-Kravis, Elizabeth; Des Portes, Vincent; Hagerman, Randi; Jacquemont, Sébastien; Charles, Perrine; Visootsak, Jeannie; Brinkman, Marc; Rerat, Karin; Koumaras, Barbara; Zhu, Liansheng; Barth, Gottfried Maria; Jaecklin, Thomas; Apostol, George; von Raison, Florian

2016-01-13

Fragile X syndrome (FXS), the most common cause of inherited intellectual disability and autistic spectrum disorder, is typically caused by transcriptional silencing of the X-linked FMR1 gene. Work in animal models has described altered synaptic plasticity, a result of the up-regulation of metabotropic glutamate receptor 5 (mGluR5)-mediated signaling, as a putative downstream effect. Post hoc analysis of a randomized, placebo-controlled, crossover phase 2 trial suggested that the selective mGluR5 antagonist mavoglurant improved behavioral symptoms in FXS patients with completely methylated FMR1 genes. We present the results of two phase 2b, multicenter, randomized, double-blind, placebo-controlled, parallel-group studies of mavoglurant in FXS, designed to confirm this result in adults (n = 175, aged 18 to 45 years) and adolescents (n = 139, aged 12 to 17 years). In both trials, participants were stratified by methylation status and randomized to receive mavoglurant (25, 50, or 100 mg twice daily) or placebo over 12 weeks. Neither of the studies achieved the primary efficacy end point of improvement on behavioral symptoms measured by the Aberrant Behavior Checklist-Community Edition using the FXS-specific algorithm (ABC-C(FX)) after 12 weeks of treatment with mavoglurant. The safety and tolerability profile of mavoglurant was as previously described, with few adverse events. Therefore, under the conditions of our study, we could not confirm the mGluR theory of FXS nor the ability of the methylation state of the FMR1 promoter to predict mavoglurant efficacy. Preclinical results suggest that future clinical trials might profitably explore initiating treatment in a younger population with longer treatment duration and longer placebo run-ins and identifying new markers to better assess behavioral and cognitive benefits. Copyright © 2016, American Association for the Advancement of Science.

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice

PubMed Central

Guo, Weirui; Molinaro, Gemma; Collins, Katie A.; Hays, Seth A.; Paylor, Richard; Worley, Paul F.; Szumlinski, Karen K.

2016-01-01

Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5R/R) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5R/R mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. SIGNIFICANCE STATEMENT Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders. PMID:26888925

Selective Disruption of Metabotropic Glutamate Receptor 5-Homer Interactions Mimics Phenotypes of Fragile X Syndrome in Mice.

PubMed

Guo, Weirui; Molinaro, Gemma; Collins, Katie A; Hays, Seth A; Paylor, Richard; Worley, Paul F; Szumlinski, Karen K; Huber, Kimberly M

2016-02-17

Altered function of the Gq-coupled, Group 1 metabotropic glutamate receptors, specifically mGlu5, is implicated in multiple mouse models of autism and intellectual disability. mGlu5 dysfunction has been most well characterized in the fragile X syndrome mouse model, the Fmr1 knock-out (KO) mouse, where pharmacological and genetic reduction of mGlu5 reverses many phenotypes. mGlu5 is less associated with its scaffolding protein Homer in Fmr1 KO mice, and restoration of mGlu5-Homer interactions by genetic deletion of a short, dominant negative of Homer, H1a, rescues many phenotypes of Fmr1 KO mice. These results suggested that disruption of mGlu5-Homer leads to phenotypes of FXS. To test this idea, we examined mice with a knockin mutation of mGlu5 (F1128R; mGlu5(R/R)) that abrogates binding to Homer. Although FMRP levels were normal, mGlu5(R/R) mice mimicked multiple phenotypes of Fmr1 KO mice, including reduced mGlu5 association with the postsynaptic density, enhanced constitutive mGlu5 signaling to protein synthesis, deficits in agonist-induced translational control, protein synthesis-independent LTD, neocortical hyperexcitability, audiogenic seizures, and altered behaviors, including anxiety and sensorimotor gating. These results reveal new roles for the Homer scaffolds in regulation of mGlu5 function and implicate a specific molecular mechanism in a complex brain disease. Abnormal function of the metabotropic, or Gq-coupled, glutamate receptor 5 (mGlu5) has been implicated in neurodevelopmental disorders, including a genetic cause of intellectual disability and autism called fragile X syndrome. In brains of a mouse model of fragile X, mGlu5 is less associated with its binding partner Homer, a scaffolding protein that regulates mGlu5 localization to synapses and its ability to activate biochemical signaling pathways. Here we show that a mouse expressing a mutant mGlu5 that cannot bind to Homer is sufficient to mimic many of the biochemical, neurophysiological, and behavioral symptoms observed in the fragile X mouse. This work provides strong evidence that Homer-mGlu5 binding contributes to symptoms associated with neurodevelopmental disorders. Copyright © 2016 the authors 0270-6474/16/362131-17$15.00/0.

Features of Fragile X Syndrome

MedlinePlus

... Since many children with FXS are interested in social interactions, they may not meet the diagnostic criteria for ... as appropriate. The core deficit in ASD is social interaction. The core deficit in FXS is intellectual function ...

A Comparison of Pragmatic Language in Boys with Autism and Fragile X Syndrome

PubMed Central

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2014-01-01

Purpose Impaired pragmatic language (i.e., language use for social interaction) is a hallmark feature of both autism spectrum disorder (ASD) and fragile X syndrome (FXS), the most common known monogenic disorder associated with ASD. However, few cross-population comparisons of ASD and FXS have been conducted, and it is unclear whether pragmatic language profiles in these conditions overlap. Method This study used semi-naturalistic and standardized assessment methods to characterize pragmatic language abilities of 29 school-aged boys with idiopathic ASD, 38 with FXS and comorbid ASD, 16 with FXS without ASD, 20 with Down syndrome and 20 with typical development. Results Similar severity of pragmatic language deficits was observed in both of the groups with ASD (idiopathic and fragile X-associated). ASD comorbidity had a detrimental effect on the pragmatic language skills of boys with FXS. Some different patterns emerged across the two pragmatic assessment tools, with more robust group differences observed in pragmatics assessed in a semi-naturalistic conversational context. Conclusions These findings have implications for pragmatic language assessment and intervention, as well as for understanding the potential role of the fragile X gene, Fragile X Mental Retardation-1, in the pragmatic language phenotype of ASD. PMID:24686468

The Role of Ionotropic Glutamate Receptors in Childhood Neurodevelopmental Disorders: Autism Spectrum Disorders and Fragile X Syndrome

PubMed Central

Uzunova, Genoveva; Hollander, Eric; Shepherd, Jason

2014-01-01

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. PMID:24533017

Autism Spectrum Disorder and Fragile X Syndrome

MedlinePlus

... Since many children with FXS are interested in social interactions, they may not meet the diagnostic criteria for ... as appropriate. The core deficit in ASD is social interaction. The core deficit in FXS is intellectual function ...

Treatments for fragile X syndrome: a closer look at the data.

PubMed

Hall, Scott S

2009-01-01

Research into the determinants and developmental course of fragile X syndrome (FXS) has made remarkable progress over the last 25 years. However, treatments to ameliorate the symptoms of FXS have been less forthcoming. While there is optimism in the field that the pace of intervention research is quickening, there has been a bias toward psychopharmacological approaches to treatment. A closer look at the data from those investigations reveals a paucity of evidence that medications can improve intellectual and adaptive functioning in FXS, or decrease associated behavioral and/or emotional issues. Work in other related disorders (e.g., autism) has shown that dramatic improvements in intellectual and adaptive functioning, as well as behavioral and emotional problems, can occur if intensive behavioral treatment is begun early in the child's life. It is hoped that future research efforts will evaluate these intensive early intervention strategies in children with FXS, perhaps in combination with pharmacological approaches.

A preliminary study of screening for risk of autism in children with fragile X syndrome: testing two risk cut-offs for the Checklist for Autism in Toddlers.

PubMed

Scambler, D J; Hepburn, S L; Hagerman, R J; Rogers, S J

2007-04-01

Risk criteria for the Checklist for Autism in Toddlers (CHAT) and modified risk criteria (i.e. the Denver Criteria) were compared in a group of children with fragile X syndrome (FXS) and autism. Participants were 17 children aged 2-4 years with DNA confirmation of FXS. Four children had autism and 13 children did not. Preliminary findings regarding the sensitivity and specificity of the CHAT for detecting risk for autism in children with FXS are as follows: using the original CHAT risk criteria, sensitivity and specificity were 50% and 100%, respectively; and using the Denver Criteria, sensitivity and specificity were 75% and 92%, respectively. The CHAT and the Denver Criteria resulted in preliminary findings suggesting high levels of sensitivity to autism in children with FXS.

Longitudinal Trajectories of Aberrant Behavior in Fragile X Syndrome

PubMed Central

Hustyi, Kristin M.; Hall, Scott S.; Jo, Booil; Lightbody, Amy A.; Reiss, Allan L.

2016-01-01

The Aberrant Behavior Checklist—Community (ABC-C; Aman, Burrow, & Wolford, 1995) has been increasingly adopted as a primary tool for measuring behavioral change in clinical trials for individuals with fragile X syndrome (FXS). To our knowledge, however, no study has documented the longitudinal trajectory of aberrant behaviors in individuals with FXS using the ABC-C. As part of a larger longitudinal study, we examined scores obtained on the ABC-C subscales for 124 children and adolescents (64 males, 60 females) with FXS who had two or more assessments (average interval between assessments was approximately 4 years). Concomitant changes in age-equivalent scores on the Vineland Adaptive Behavior Scales (VABS) were also examined. As expected for an X-linked genetic disorder, males with FXS obtained significantly higher scores on all subscales of the ABC-C and significantly lower age-equivalent scores on the VABS than females with FXS. In both males and females with FXS, scores on the Irritability/Agitation and Hyperactivity/Noncompliance subscales of the ABC-C decreased significantly with age, with little to no change occurring over time on the Lethargy/Social Withdrawal, Stereotypic Behavior, and Inappropriate Speech subscales. The decrease in scores on the Hyperactivity/Noncompliance domain was significantly greater for males than for females. In both males and females, age-equivalent scores on the VABS increased significantly over this developmental period. These results establish a basis upon which to evaluate long-term outcomes from intervention-based research. However, longitudinal direct observational studies are needed to establish whether the severity of problem behavior actually decreases over time in this population. PMID:25129200

Assessing the Fragile X Syndrome Newborn Screening Landscape.

PubMed

Riley, Catharine; Wheeler, Anne

2017-06-01

Fragile X syndrome (FXS) is the most common known inherited form of intellectual disability. Early identification is an important step in linking FXS individuals with appropriate and timely medical and social services. Newborn screening (NBS) is 1 approach that has been used for other conditions to facilitate early identification. A literature review was conducted to identify issues, barriers, challenges, and approaches to addressing challenges related to NBS for FXS. Search terms included: fragile X syndrome, FMR1, newborn screening, screening, and genetic testing. To supplement the literature review, 9 key informant interviews were conducted. Information gathered through these interviews supplemented what was identified in the literature. Information from both the literature review and supplemental interviews was reviewed by 3 researchers who discussed and came to consensus on thematic areas and categorization of issues. The barriers and challenges related to NBS for FXS identified in the literature and by experts and stakeholders are categorized into 5 thematic areas: public health burden, treatment, timing, screening/testing methodologies, and translating results. Summaries of these issues and barriers are provided, along with potential approaches to addressing them. The issues and barriers described in this article highlight limited areas of knowledge that need be addressed to improve our understanding of FXS and the potential benefit of NBS. The landscape of NBS for FXS could be influenced by a series of research findings over time or a larger breakthrough that demonstrates an effective targeted treatment that has to be implemented early in life. Copyright © 2017 by the American Academy of Pediatrics.

A comparison of family financial and employment impacts of fragile X syndrome, autism spectrum disorders, and intellectual disability.

PubMed

Ouyang, Lijing; Grosse, Scott D; Riley, Catharine; Bolen, Julie; Bishop, Ellen; Raspa, Melissa; Bailey, Donald B

2014-07-01

This study compares the family financial and employment impacts of having a child with fragile X syndrome (FXS), autism spectrum disorder (ASD), or intellectual disabilities (ID). Data from a 2011 national survey of families of children with FXS were matched with data from the National Survey of Children with Special Health Care Needs 2009-2010 to form four analytic groups: children with FXS (n=189), children with special health care needs with ASD only (n=185), ID only (n=177), or both ASD and ID (n=178). Comparable percentages of parents of children with FXS (60%) and parents of children with both ASD and ID (52%) reported that their families experienced a financial burden as a result of the condition, both of which were higher than the percentages of parents of children with ASD only (39%) or ID only (29%). Comparable percentages of parents of children with FXS (40%) and parents of children with both ASD and ID (46%) reported quitting employment because of the condition, both of which were higher than the percentages of parents of children with ID only (25%) or ASD only (25%). In multivariate analyses controlling for co-occurring conditions and functional difficulties and stratified by age, adjusted odds ratios for the FXS group aged 12-17 years were significantly elevated for financial burden (2.73, 95% CI 1.29-5.77), quitting employment (2.58, 95% CI 1.18-5.65) and reduced hours of work (4.34, 95% CI 2.08-9.06) relative to children with ASD only. Among children aged 5-11 years, the adjusted odds ratios for the FXS group were elevated but statistically insignificant for financial burden (1.63, 95% CI 0.85-3.14) and reducing hours of work (1.34, 95% CI 0.68-2.63) relative to children with ASD only. Regardless of condition, co-occurring anxiety or seizures, limits in thinking, reasoning, or learning ability, and more irritability were significantly associated with more caregiver financial and employment impacts. Proper management of anxiety or seizures and functional difficulties of children with FXS or other developmental disabilities may be important in alleviating adverse family caregiver impacts. Published by Elsevier Ltd.

Signaling of noncomprehension in communication breakdowns in fragile X syndrome, Down syndrome, and autism spectrum disorder.

PubMed

Martin, Gary E; Barstein, Jamie; Hornickel, Jane; Matherly, Sara; Durante, Genna; Losh, Molly

The ability to indicate a failure to understand a message is a critical pragmatic (social) language skill for managing communication breakdowns and supporting successful communicative exchanges. The current study examined the ability to signal noncomprehension across different types of confusing message conditions in children and adolescents with fragile X syndrome (FXS), Down syndrome (DS), autism spectrum disorder (ASD), and typical development (TD). Controlling for nonverbal mental age and receptive vocabulary skills, youth with comorbid FXS and ASD and those with DS were less likely than TD controls to signal noncomprehension of confusing messages. Youth with FXS without ASD and those with idiopathic ASD did not differ from controls. No sex differences were detected in any group. Findings contribute to current knowledge of pragmatic profiles in different forms of genetically-based neurodevelopmental disorders associated with intellectual disability, and the role of sex in the expression of such profiles. Upon completion of this article, readers will have learned about: (1) the social-communicative profiles of youth with FXS, DS, and ASD, (2) the importance of signaling noncomprehension in response to a confusing message, and (3) the similarities and differences in noncomprehension signaling in youth with FXS (with and without ASD), DS, idiopathic ASD, and TD. Copyright © 2017 Elsevier Inc. All rights reserved.

Joint Engagement and Early Language in Young Children With Fragile X Syndrome

PubMed Central

Brady, Nancy C.; Fleming, Kandace K.; Warren, Steven F.

2016-01-01

Purpose In this study, we examine joint engagement (JE) in young children with fragile X syndrome (FXS) and its relationship to language abilities and autism spectrum disorder symptomatology at 24 to 36 months (toddler period) and 59 to 68 months (child period). Method Participants were 28 children with FXS (24 boys, four girls) and their mothers. Videotaped home observations were conducted during the toddler period and coded for JE. Language abilities were measured at both ages from a developmental assessment, a functional measure, and from a language sample. The Childhood Autism Rating Scale (Schopler, Reichler, & Renner, 1988) was completed at both ages. Results Children with FXS spent more time in supported JE than in coordinated JE. Using a weighted JE variable, we found that children with FXS who had higher weighted JE scores also had more advanced expressive language skills at both the toddler and child periods. Weighted JE was negatively related to autism symptomatology in the toddler period. Conclusion This study provides evidence that children with FXS who use more JE also have more advanced expressive language skills in early development. Therefore, existing early interventions that target JE behaviors may be effective for promoting language, social communication, and social interaction in this population. PMID:27681878

Integrative cortical dysfunction and pervasive motion perception deficit in fragile X syndrome.

PubMed

Kogan, C S; Bertone, A; Cornish, K; Boutet, I; Der Kaloustian, V M; Andermann, E; Faubert, J; Chaudhuri, A

2004-11-09

Fragile X syndrome (FXS) is associated with neurologic deficits recently attributed to the magnocellular pathway of the lateral geniculate nucleus. To test the hypotheses that FXS individuals 1) have a pervasive visual motion perception impairment affecting neocortical circuits in the parietal lobe and 2) have deficits in integrative neocortical mechanisms necessary for perception of complex stimuli. Psychophysical tests of visual motion and form perception defined by either first-order (luminance) or second-order (texture) attributes were used to probe early and later occipito-temporal and occipito-parietal functioning. When compared to developmental- and age-matched controls, FXS individuals displayed severe impairments in first- and second-order motion perception. This deficit was accompanied by near normal perception for first-order form stimuli but not second-order form stimuli. Impaired visual motion processing for first- and second-order stimuli suggests that both early- and later-level neurologic function of the parietal lobe are affected in Fragile X syndrome (FXS). Furthermore, this deficit likely stems from abnormal input from the magnocellular compartment of the lateral geniculate nucleus. Impaired visual form and motion processing for complex visual stimuli with normal processing for simple (i.e., first-order) form stimuli suggests that FXS individuals have normal early form processing accompanied by a generalized impairment in neurologic mechanisms necessary for integrating all early visual input.

Progress toward therapeutic potential for AFQ056 in Fragile X syndrome.

PubMed

Sourial, Mary; Cheng, Connie; Doering, Laurie C

2013-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability and the leading single-gene cause of autism. It is caused by the lack of production of the Fragile X mental retardation protein (FMRP), resulting in cognitive deficits, hyperactivity, and autistic behaviors. Breakthrough advances in potential therapy for FXS followed the discovery that aberrant group 1 metabotropic glutamate receptor (mGluR) signaling is an important constituent of the pathophysiology of the syndrome. Research has indicated that upon neuronal stimulation, FMRP acts downstream of group 1 mGluRs (mGluRs1/5) to inhibit protein synthesis, long-term depression, and α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor internalization. To offset the deficits caused by the lack of FMRP, many pharmaceutical companies have designed medicinal drugs to target the unrestrained stimulation of mGluR5 signaling in FXS. Indeed, promising results from animal and clinical studies suggest that mGluR5 antagonists such as AFQ056 can successfully correct many of the deficits in FXS. In this review, we cover the animal studies performed to date that test the role of AFQ056 as a selective mGluR5 antagonist to alleviate the phenotypes of FXS.

Signaling of Noncomprehension in Communication Breakdowns in Fragile X Syndrome, Down Syndrome, and Autism Spectrum Disorder

PubMed Central

Martin, Gary E.; Barstein, Jamie; Hornickel, Jane; Matherly, Sara; Durante, Genna; Losh, Molly

2017-01-01

The ability to indicate a failure to understand a message is a critical pragmatic (social) language skill for managing communication breakdowns and supporting successful communicative exchanges. The current study examined the ability to signal noncomprehension across different types of confusing message conditions in children and adolescents with fragile X syndrome (FXS), Down syndrome (DS), autism spectrum disorder (ASD), and typical development (TD). Controlling for nonverbal mental age and receptive vocabulary skills, youth with comorbid FXS and ASD and those with DS were less likely than TD controls to signal noncomprehension of confusing messages. Youth with FXS without ASD and those with idiopathic ASD did not differ from controls. No sex differences were detected in any group. Findings contribute to current knowledge of pragmatic profiles in different forms of genetically-based neurodevelopmental disorders associated with intellectual disability, and the role of sex in the expression of such profiles. Learning Outcomes Upon completion of this article, readers will have learned about: (1) the social-communicative profiles of youth with FXS, DS, and ASD, (2) the importance of signaling noncomprehension in response to a confusing message, and (3) the similarities and differences in noncomprehension signaling in youth with FXS (with and without ASD), DS, idiopathic ASD, and TD. PMID:28161297

Melatonin as a Novel Interventional Candidate for Fragile X Syndrome with Autism Spectrum Disorder in Humans.

PubMed

Won, Jinyoung; Jin, Yunho; Choi, Jeonghyun; Park, Sookyoung; Lee, Tae Ho; Lee, Sang-Rae; Chang, Kyu-Tae; Hong, Yonggeun

2017-06-20

Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation ( fmr ) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety of physiological and behavioral abnormalities. This disorder is also correlated with clock components underlying behavioral circadian rhythms and, thus, a mutation of the fmr gene can result in disturbed sleep patterns and altered circadian rhythms. As a result, FXS with ASD individuals may experience dysregulation of melatonin synthesis and alterations in melatonin-dependent signaling pathways that can impair vigilance, learning, and memory abilities, and may be linked to autistic behaviors such as abnormal anxiety responses. Although a wide variety of possible causes, symptoms, and clinical features of ASD have been studied, the correlation between altered circadian rhythms and FXS with ASD has yet to be extensively investigated. Recent studies have highlighted the impact of melatonin on the nervous, immune, and metabolic systems and, even though the utilization of melatonin for sleep dysfunctions in ASD has been considered in clinical research, future studies should investigate its neuroprotective role during the developmental period in individuals with ASD. Thus, the present review focuses on the regulatory circuits involved in the dysregulation of melatonin and disruptions in the circadian system in individuals with FXS with ASD. Additionally, the neuroprotective effects of melatonin intervention therapies, including improvements in neuroplasticity and physical capabilities, are discussed and the molecular mechanisms underlying this disorder are reviewed. The authors suggest that melatonin may be a useful treatment for FXS with ASD in terms of alleviating the adverse effects of variations in the circadian rhythm.

Melatonin as a Novel Interventional Candidate for Fragile X Syndrome with Autism Spectrum Disorder in Humans

PubMed Central

Won, Jinyoung; Jin, Yunho; Choi, Jeonghyun; Park, Sookyoung; Lee, Tae Ho; Lee, Sang-Rae; Chang, Kyu-Tae; Hong, Yonggeun

2017-01-01

Fragile X syndrome (FXS) is the most common monogenic form of autism spectrum disorder (ASD). FXS with ASD results from the loss of fragile X mental retardation (fmr) gene products, including fragile X mental retardation protein (FMRP), which triggers a variety of physiological and behavioral abnormalities. This disorder is also correlated with clock components underlying behavioral circadian rhythms and, thus, a mutation of the fmr gene can result in disturbed sleep patterns and altered circadian rhythms. As a result, FXS with ASD individuals may experience dysregulation of melatonin synthesis and alterations in melatonin-dependent signaling pathways that can impair vigilance, learning, and memory abilities, and may be linked to autistic behaviors such as abnormal anxiety responses. Although a wide variety of possible causes, symptoms, and clinical features of ASD have been studied, the correlation between altered circadian rhythms and FXS with ASD has yet to be extensively investigated. Recent studies have highlighted the impact of melatonin on the nervous, immune, and metabolic systems and, even though the utilization of melatonin for sleep dysfunctions in ASD has been considered in clinical research, future studies should investigate its neuroprotective role during the developmental period in individuals with ASD. Thus, the present review focuses on the regulatory circuits involved in the dysregulation of melatonin and disruptions in the circadian system in individuals with FXS with ASD. Additionally, the neuroprotective effects of melatonin intervention therapies, including improvements in neuroplasticity and physical capabilities, are discussed and the molecular mechanisms underlying this disorder are reviewed. The authors suggest that melatonin may be a useful treatment for FXS with ASD in terms of alleviating the adverse effects of variations in the circadian rhythm. PMID:28632163

Social Approach and Emotion Recognition in Fragile X Syndrome

ERIC Educational Resources Information Center

Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

2014-01-01

Evidence is emerging that individuals with Fragile X syndrome (FXS) display emotion recognition deficits, which may contribute to their significant social difficulties. The current study investigated the emotion recognition abilities, and social approachability judgments, of FXS individuals when processing emotional stimuli. Relative to…

FMR1 Epigenetic Silencing Commonly Occurs in Undifferentiated Fragile X-Affected Embryonic Stem Cells

PubMed Central

Avitzour, Michal; Mor-Shaked, Hagar; Yanovsky-Dagan, Shira; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Levy-Lahad, Ephrat; Epsztejn-Litman, Silvina; Eiges, Rachel

2014-01-01

Summary Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5′-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases. PMID:25418717

FMR1 epigenetic silencing commonly occurs in undifferentiated fragile X-affected embryonic stem cells.

PubMed

Avitzour, Michal; Mor-Shaked, Hagar; Yanovsky-Dagan, Shira; Aharoni, Shira; Altarescu, Gheona; Renbaum, Paul; Eldar-Geva, Talia; Schonberger, Oshrat; Levy-Lahad, Ephrat; Epsztejn-Litman, Silvina; Eiges, Rachel

2014-11-11

Fragile X syndrome (FXS) is the most common heritable form of cognitive impairment. It results from epigenetic silencing of the X-linked FMR1 gene by a CGG expansion in its 5'-untranslated region. Taking advantage of a large set of FXS-affected human embryonic stem cell (HESC) lines and isogenic subclones derived from them, we show that FMR1 hypermethylation commonly occurs in the undifferentiated state (six of nine lines, ranging from 24% to 65%). In addition, we demonstrate that hypermethylation is tightly linked with FMR1 transcriptional inactivation in undifferentiated cells, coincides with loss of H3K4me2 and gain of H3K9me3, and is unrelated to CTCF binding. Taken together, these results demonstrate that FMR1 epigenetic gene silencing takes place in FXS HESCs and clearly highlights the importance of examining multiple cell lines when investigating FXS and most likely other epigenetically regulated diseases.

Utility of the Hebb-Williams Maze Paradigm for Translational Research in Fragile X Syndrome: A Direct Comparison of Mice and Humans.

PubMed

Boutet, Isabelle; Collin, Charles A; MacLeod, Lindsey S; Messier, Claude; Holahan, Matthew R; Berry-Kravis, Elizabeth; Gandhi, Reno M; Kogan, Cary S

2018-01-01

To generate meaningful information, translational research must employ paradigms that allow extrapolation from animal models to humans. However, few studies have evaluated translational paradigms on the basis of defined validation criteria. We outline three criteria for validating translational paradigms. We then evaluate the Hebb-Williams maze paradigm (Hebb and Williams, 1946; Rabinovitch and Rosvold, 1951) on the basis of these criteria using Fragile X syndrome (FXS) as model disease. We focused on this paradigm because it allows direct comparison of humans and animals on tasks that are behaviorally equivalent (criterion #1) and because it measures spatial information processing, a cognitive domain for which FXS individuals and mice show impairments as compared to controls (criterion #2). We directly compared the performance of affected humans and mice across different experimental conditions and measures of behavior to identify which conditions produce comparable patterns of results in both species. Species differences were negligible for Mazes 2, 4, and 5 irrespective of the presence of visual cues, suggesting that these mazes could be used to measure spatial learning in both species. With regards to performance on the first trial, which reflects visuo-spatial problem solving, Mazes 5 and 9 without visual cues produced the most consistent results. We conclude that the Hebb-Williams mazes paradigm has the potential to be utilized in translational research to measure comparable cognitive functions in FXS humans and animals (criterion #3).

Attention and Language in Fragile X

ERIC Educational Resources Information Center

Cornish, Kim; Sudhalter, Vicki; Turk, Jeremy

2004-01-01

Fragile X syndrome (FXS) is a well-recognized cause of mental retardation and developmental delay in males. Alongside the well-documented clinical characteristics of the condition, recent advances in technology and methodology have begun to define FXS at a number of different levels: genetic, brain structure and function, cognition, and behavior.…

Emotion Potentiated Startle in Fragile X Syndrome

ERIC Educational Resources Information Center

Ballinger, Elizabeth C.; Cordeiro, Lisa; Chavez, Alyssa D.; Hagerman, Randi J.; Hessl, David

2014-01-01

Social avoidance and anxiety are prevalent in fragile X syndrome (FXS) and are potentially mediated by the amygdala, a brain region critical for social behavior. Unfortunately, functional brain resonance imaging investigation of the amygdala in FXS is limited by the difficulties experienced by intellectually impaired and anxious participants. We…

Phonological Awareness and Reading in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Adlof, Suzanne M.; Klusek, Jessica; Shinkareva, Svetlana V.; Robinson, Marissa L.; Roberts, Jane E.

2015-01-01

Background: Reading delays are well documented in children with fragile X syndrome (FXS), but few studies have examined linguistic precursors of reading in this population. This study examined the longitudinal development of phonological awareness and its relationship with basic reading in boys with FXS. Individual differences in genetic,…

The Expressed Emotion of Mothers of Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Coleman, Jeanine M.

2010-01-01

A review of the literature revealed that mothers with children with fragile X syndrome (FXS) face many challenges, including managing their child's behavior which is a defining characteristic of children with FXS (Epstein, Riley, & Sobesky, 2002). Parents and professionals have become increasingly aware through research and everyday experiences…

Psychopharmacology in Fragile X Syndrome--Present and Future

ERIC Educational Resources Information Center

Berry-Kravis, Elizabeth; Potanos, Kristina

2004-01-01

In addition to cognitive disability, fragile X syndrome (FXS) is associated with behavioral problems that are often functionally limiting. There are few controlled trials to guide treatment; however, available information does suggest that medications can be quite helpful for a number of categories of behavioral disturbance in FXS. Specifically,…

Imitation in Fragile X Syndrome: Implications for Autism

ERIC Educational Resources Information Center

Macedoni-Luksic, Marta; Greiss-Hess, Laura; Rogers, Sally J.; Gosar, David; Lemons-Chitwood, Kerrie; Hagerman, Randi

2009-01-01

To address the specific impairment of imitation in autism, the imitation abilities of 22 children with fragile X syndrome (FXS) with and without autism were compared. Based on previous research, we predicted that children with FXS and autism would have significantly more difficulty with non-meaningful imitation tasks. After controlling for…

Profiling Fragile X Syndrome in Males: Strengths and Weaknesses in Cognitive Abilities

ERIC Educational Resources Information Center

Van der Molen, M. J. W.; Huizinga, M.; Huizenga, H. M.; Ridderinkhof, K. R.; Van der Molen, M. W.; Hamel, B. J. C.; Curfs, L. M. G.; Ramakers, G. J. A.

2010-01-01

The present study examined the cognitive profile in Fragile X Syndrome (FXS) males, and investigated whether cognitive profiles are similar for FXS males at different levels of intellectual functioning. Cognitive abilities in non-verbal, verbal, memory and executive functioning domains were contrasted to both a non-verbal and verbal mental age…

Communication in Young Children with Fragile X Syndrome: A Qualitative Study of Mothers' Perspectives

ERIC Educational Resources Information Center

Brady, Nancy; Skinner, Debra; Roberts, Joanne; Hennon, Elizabeth

2006-01-01

Purpose: To provide descriptive and qualitative information about communication in young children with fragile X syndrome (FXS) and about how families react to and accommodate communication differences in their children. Method: In-depth interviews were conducted with 55 mothers of young children with FXS. Interviewers asked mothers to describe…

Biobehavioral Indicators of Social Fear in Young Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Tonnsen, Bridgette L.; Shinkareva, Svetlana V.; Deal, Sara C.; Hatton, Deborah D.; Roberts, Jane E.

2013-01-01

Anxiety is among the most impairing conditions associated with Fragile X syndrome (FXS) and is putatively linked to atypical physiological arousal. However, few studies have examined this association in young children with FXS. The authors examined whether patterns of arousal and behavior during an experimental stranger approach paradigm differ…

Relationships between Early Gestures and Later Language in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Flenthrope, Jennifer L.; Brady, Nancy C.

2010-01-01

Purpose: The authors hypothesized that significant positive relationships would exist between early gesture use and later language attainments in children with fragile X syndrome (FXS), as has been reported in studies with other populations. Method: Participants were young children with FXS and limited expressive language (21 boys, 4 girls),…

Physiological Correlates of Maternal Responsivity in Mothers of Preschoolers with Fragile X Syndrome

ERIC Educational Resources Information Center

Robinson, Ashley N.; Roberts, Jane E.; Brady, Nancy C.; McQuillin, Samuel D.; Warren, Steven F.

2016-01-01

The present study examined the relationship between salivary cortisol and maternal responsiveness in mothers of boys with fragile X syndrome (FXS). Maternal responsivity is strongly associated with child outcomes, and children with FXS are at risk for compromised development due to intellectual disability and problem behavior. Increased…

Language Development in Individuals with Fragile X Syndrome

ERIC Educational Resources Information Center

Finestack, Lizbeth H.; Richmond, Erica K.; Abbeduto, Leonard

2009-01-01

Fragile X syndrome (FXS) is the leading inherited cause of intellectual disability. The syndrome is caused by a single gene mutation on the X chromosome. Although individual differences are large, most individuals with FXS display weaknesses across all language and literacy domains compared with peers of the same chronological age with typical…

How Does Fragile X Syndrome Affect Speech and Language Skills? FPG Snapshot. Number 51. January 2008

ERIC Educational Resources Information Center

FPG Child Development Institute, 2008

2008-01-01

Children with fragile X syndrome (FXS), the most common known inherited cause of intellectual disability, typically experience communication difficulties. Children with other intellectual disabilities such as Down syndrome also experience communication difficulties. Further, many boys with FXS (some estimates are as high as 35 percent) also are…

Noncomprehension Signaling in Males and Females with Fragile X Syndrome

ERIC Educational Resources Information Center

Thurman, Angela John; Kover, Sara T.; Brown, W. Ted; Harvey, Danielle J.; Abbeduto, Leonard

2017-01-01

Purpose: This study used a prospective longitudinal design to evaluate the trajectory and predictors of noncomprehension signaling in male and female youth with fragile X syndrome (FXS). Method: A direction-following task in which some of the directions were inadequate was administered. Participants were 52 youth (36 boys, 16 girls) with FXS. Upon…

Social Behavior and Cortisol Reactivity in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hessl, David; Glaser, Bronwyn; Dyer-Friedman, Jennifer; Reiss, Allan L.

2006-01-01

Objective: To examine the association between limbic-hypothalamic-pituitary-adrenal (L-HPA) axis reactivity and social behavior in children with fragile X syndrome (FXS). Method: Salivary cortisol changes and concurrent anxiety-related behaviors consistent with the behavioral phenotype of FXS were measured in 90 children with the fragile X full…

Social Approach and Autistic Behavior in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Roberts, Jane E.; Weisenfeld, Leigh Anne H.; Hatton, Deborah D.; Heath, Morgan; Kaufmann, Walter E.

2007-01-01

Social avoidance is a core phenotypic characteristic of fragile X syndrome (FXS) that has critical cognitive and social consequences. However, no study has examined modulation of multiple social avoidant behaviors in children with FXS. In the current study, we introduce the "Social Approach Scale" (SAS), an observation scale that includes physical…

Clinical and molecular implications of mosaicism in FMR1 full mutations

PubMed Central

Pretto, Dalyir; Yrigollen, Carolyn M.; Tang, Hiu-Tung; Williamson, John; Espinal, Glenda; Iwahashi, Chris K.; Durbin-Johnson, Blythe; Hagerman, Randi J.; Hagerman, Paul J.; Tassone, Flora

2014-01-01

Expansions of more than 200 CGG repeats (full mutation) in the FMR1 gene give rise to fragile X syndrome (FXS) through a process that generally involves hypermethylation of the FMR1 promoter region and gene silencing, resulting in absence of expression of the encoded protein, FMRP. However, mosaicism with alleles differing in size and extent of methylation often exist within or between tissues of individuals with FXS. In the current work, CGG-repeat lengths and methylation status were assessed for eighteen individuals with FXS, including 13 mosaics, for which peripheral blood cells (PBMCs) and primary fibroblast cells were available. Our results show that for both PBMCs and fibroblasts, FMR1 mRNA and FMRP expression are directly correlated with the percent of methylation of the FMR1 allele. In addition, Full Scale IQ scores were inversely correlated with the percent methylation and positively correlated with higher FMRP expression. These latter results point toward a positive impact on cognition for full mutation mosaics with lower methylation compared to individuals with fully methylated, full mutation alleles. However, we did not observe a significant reduction in the number of seizures, nor in the severity of hyperactivity or autism spectrum disorder, among individuals with mosaic genotypes in the presentation of FXS. These observations suggest that low, but non-zero expression of FMRP may be sufficient to positively impact cognitive function in individuals with FXS, with methylation mosaicism (lowered methylation fraction) contributing to a more positive clinical outcome. PMID:25278957

The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome.

PubMed

Wirojanan, Juthamas; Jacquemont, Sebastien; Diaz, Rafael; Bacalman, Susan; Anders, Thomas F; Hagerman, Randi J; Goodlin-Jones, Beth L

2009-04-15

To determine the efficacy of melatonin on sleep problems in children with autistic spectrum disorder (ASD) and fragile X syndrome (FXS). A 4-week, randomized, double blind, placebo-controlled, crossover design was conducted following a 1-week baseline period. Either melatonin, 3 mg, or placebo was given to participants for 2 weeks and then alternated for another 2 weeks. Sleep variables, including sleep duration, sleep-onset time, sleep-onset latency time, and the number of night awakenings, were recorded using an Actiwatch and from sleep diaries completed by parents. All participants had been thoroughly assessed for ASD and also had DNA testing for the diagnosis of FXS. Data were successfully obtained from the 12 of 18 subjects who completed the study (11 males, age range 2 to 15.25 years, mean 5.47, SD 3.6). Five participants met diagnostic criteria for ASD, 3 for FXS alone, 3 for FXS and ASD, and 1 for fragile X premutation. Eight out of 12 had melatonin first. The conclusions from a nonparametric repeated-measures technique indicate that mean night sleep duration was longer on melatonin than placebo by 21 minutes (p = .02), mean sleep-onset latency was shorter by 28 minutes (p = .0001), and mean sleep-onset time was earlier by 42 minutes (p = .02). The results of this study support the efficacy and tolerability of melatonin treatment for sleep problems in children with ASD and FXS.

Unraveling unusual X-chromosome patterns during fragile-X syndrome genetic testing.

PubMed

Esposito, Gabriella; Tremolaterra, Maria Roberta; Savarese, Maria; Spiniello, Michele; Patrizio, Maria Pia; Lombardo, Barbara; Pastore, Lucio; Salvatore, Francesco; Carsana, Antonella

2018-01-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability (ID). Together with fragile X-associated tremor and ataxia (FXTAS) and fragile X-associated premature ovarian failure (POF)/primary ovarian insufficiency (POI), FXS depends on dysfunctional expression of the FMR1 gene on Xq27.3. In most cases, FXS is caused by a >200 CGG repeats in FMR1 5'-untranslated region (UTR) and by promoter hypermethylation that results in gene silencing. Males and females with unmethylated premutated alleles (repeats between 55 and 200) are at risk for FXTAS and POF/POI. FXS molecular testing relied on PCR and methylation-specific Southern blot analysis of the FMR1 5'UTR. Atypical Southern blot patterns were studied by X-chromosome microsatellite analysis, copy number dosage at DMD locus, amelogenin gender-marker analysis and array-comparative genomic hybridization (array-CGH). Six men affected by ID and three women affected by ID and POF/POI underwent FXS molecular testing. They had normal FMR1 CGG repeats, but atypical X chromosome patterns. Further investigations revealed that the six males had Klinefelter syndrome (XXY), one female was a Turner mosaic (X0/XX) and two women had novel rearrangements involving X chromosome. Diagnostic investigation of atypical patterns at FMR1 locus can address patients and/or their relatives to further verify the condition by performing karyotyping and/or array-CGH. Copyright © 2017. Published by Elsevier B.V.

Fragile X Mental Retardation Protein Regulates Activity-Dependent Membrane Trafficking and Trans-Synaptic Signaling Mediating Synaptic Remodeling

PubMed Central

Sears, James C.; Broadie, Kendal

2018-01-01

Fragile X syndrome (FXS) is the leading monogenic cause of autism and intellectual disability. The disease arises through loss of fragile X mental retardation protein (FMRP), which normally exhibits peak expression levels in early-use critical periods, and is required for activity-dependent synaptic remodeling during this transient developmental window. FMRP canonically binds mRNA to repress protein translation, with targets that regulate cytoskeleton dynamics, membrane trafficking, and trans-synaptic signaling. We focus here on recent advances emerging in these three areas from the Drosophila disease model. In the well-characterized central brain mushroom body (MB) olfactory learning/memory circuit, FMRP is required for activity-dependent synaptic remodeling of projection neurons innervating the MB calyx, with function tightly restricted to an early-use critical period. FMRP loss is phenocopied by conditional removal of FMRP only during this critical period, and rescued by FMRP conditional expression only during this critical period. Consistent with FXS hyperexcitation, FMRP loss defects are phenocopied by heightened sensory experience and targeted optogenetic hyperexcitation during this critical period. FMRP binds mRNA encoding Drosophila ESCRTIII core component Shrub (human CHMP4 homolog) to restrict Shrub translation in an activity-dependent mechanism only during this same critical period. Shrub mediates endosomal membrane trafficking, and perturbing Shrub expression is known to interfere with neuronal process pruning. Consistently, FMRP loss and Shrub overexpression targeted to projection neurons similarly causes endosomal membrane trafficking defects within synaptic boutons, and genetic reduction of Shrub strikingly rescues Drosophila FXS model defects. In parallel work on the well-characterized giant fiber (GF) circuit, FMRP limits iontophoretic dye loading into central interneurons, demonstrating an FMRP role controlling core neuronal properties through the activity-dependent repression of translation. In the well-characterized Drosophila neuromuscular junction (NMJ) model, developmental synaptogenesis and activity-dependent synaptic remodeling both require extracellular matrix metalloproteinase (MMP) enzymes interacting with the heparan sulfate proteoglycan (HSPG) glypican dally-like protein (Dlp) to restrict trans-synaptic Wnt signaling, with FXS synaptogenic defects alleviated by both MMP and HSPG reduction. This new mechanistic axis spanning from activity to FMRP to HSPG-dependent MMP regulation modulates activity-dependent synaptogenesis. We discuss future directions for these mechanisms, and intersecting research priorities for FMRP in glial and signaling interactions. PMID:29375303

Selective Deletion of Astroglial FMRP Dysregulates Glutamate Transporter GLT1 and Contributes to Fragile X Syndrome Phenotypes In Vivo.

PubMed

Higashimori, Haruki; Schin, Christina S; Chiang, Ming Sum R; Morel, Lydie; Shoneye, Temitope A; Nelson, David L; Yang, Yongjie

2016-07-06

How the loss of fragile X mental retardation protein (FMRP) in different brain cell types, especially in non-neuron glial cells, induces fragile X syndrome (FXS) phenotypes has just begun to be understood. In the current study, we generated inducible astrocyte-specific Fmr1 conditional knock-out mice (i-astro-Fmr1-cKO) and restoration mice (i-astro-Fmr1-cON) to study the in vivo modulation of FXS synaptic phenotypes by astroglial FMRP. We found that functional expression of glutamate transporter GLT1 is 40% decreased in i-astro-Fmr1-cKO somatosensory cortical astrocytes in vivo, which can be fully rescued by the selective re-expression of FMRP in astrocytes in i-astro-Fmr1-cON mice. Although the selective loss of astroglial FMRP only modestly increases spine density and length in cortical pyramidal neurons, selective re-expression of FMRP in astrocytes significantly attenuates abnormal spine morphology in these neurons of i-astro-Fmr1-cON mice. Moreover, we found that basal protein synthesis levels and immunoreactivity of phosphorylated S6 ribosomal protein (p-s6P) is significantly increased in i-astro-Fmr1-cKO mice, while the enhanced cortical protein synthesis observed in Fmr1 KO mice is mitigated in i-astro-Fmr1-cON mice. Furthermore, ceftriaxone-mediated upregulation of surface GLT1 expression restores functional glutamate uptake and attenuates enhanced neuronal excitability in Fmr1 KO mice. In particular, ceftriaxone significantly decreases the growth rate of abnormally accelerated body weight and completely corrects spine abnormality in Fmr1 KO mice. Together, these results show that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, presumably through dysregulated astroglial glutamate transporter GLT1 and impaired glutamate uptake. These results suggest the involvement of astrocyte-mediated mechanisms in the pathogenesis of FXS. Previous studies to understand how the loss of function of fragile X mental retardation protein (FMRP) causes fragile X syndrome (FXS) have largely focused on neurons; whether the selective loss of astroglial FMRP in vivo alters astrocyte functions and contributes to the pathogenesis of FXS remain essentially unknown. This has become a long-standing unanswered question in the fragile X field, which is also relevant to autism pathogenesis. Our current study generated astrocyte-specific Fmr1 conditional knock-out and restoration mice, and provided compelling evidence that the selective loss of astroglial FMRP contributes to cortical synaptic deficits in FXS, likely through the dysregulated astroglial glutamate transporter GLT1 expression and impaired glutamate uptake. These results demonstrate previously undescribed astrocyte-mediated mechanisms in the pathogenesis of FXS. Copyright © 2016 the authors 0270-6474/16/367080-16$15.00/0.

Motor Abilities of Children Diagnosed with Fragile X Syndrome with and without Autism

ERIC Educational Resources Information Center

Zingerevich, C.; Greiss-Hess, L.; Lemons-Chitwood, K.; Harris, S. W.; Hessl, D.; Cook, K.; Hagerman, Randi J.

2009-01-01

Background: Previous studies suggested that children diagnosed with fragile X syndrome (FXS) often meet criteria for autism or PDD. This study describes the fine motor abilities of children diagnosed with FXS with and without autism spectrum disorder, and compares the motor scores of those groups controlling for cognitive level. Method:…

Growth of Expressive Syntax in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Komesidou, Rouzana; Brady, Nancy C.; Fleming, Kandace; Esplund, Amy; Warren, Steven F.

2017-01-01

Purpose: This research explored syntactic growth in children with fragile X syndrome (FXS) over a 5-year period, and variability in growth in relation to autism symptoms, nonverbal cognition, maternal responsivity, and gender. Method: Language samples at 4 time points from 39 children with FXS, 31 boys and 8 girls, were analyzed using the Index of…

Knowledge and Perceptions about Fragile X Syndrome: Implications for Diagnosis, Intervention, and Research

ERIC Educational Resources Information Center

Finucane, Brenda; Haas-Givler, Barbara; Simon, Elliott W.

2013-01-01

We surveyed 439 professionals in the field of autism to assess their knowledge and perceptions about fragile X syndrome (FXS) and related issues. Almost half had worked with at least one child diagnosed with FXS, yet most lacked basic knowledge about the condition, underestimated its significance in the etiology of autism spectrum disorders, and…

Language Development in School-Age Girls with Fragile X Syndrome

ERIC Educational Resources Information Center

Sterling, A.; Abbeduto, L.

2012-01-01

Background: Girls with fragile X syndrome (FXS) have a wide range of cognitive and language abilities. The range of language outcomes experienced by girls with FXS, however, has been relatively unexplored. The purpose of this exploratory study was to examine receptive and expressive language, with a focus on vocabulary and syntax, in a group of…

Joint Engagement and Early Language in Young Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hahn, Laura J.; Brady, Nancy C.; Fleming, Kandace; Warren, Steven F.

2016-01-01

Purpose: In this study, we examine joint engagement (JE) in young children with fragile X syndrome (FXS) and its relationship to language abilities and autism spectrum disorder symptomatology at 24 to 36 months (toddler period) and 59 to 68 months (child period). Method: Participants were 28 children with FXS (24 boys, four girls) and their…

Visual Processing of Faces in Individuals with Fragile X Syndrome: An Eye Tracking Study

ERIC Educational Resources Information Center

Farzin, Faraz; Rivera, Susan M.; Hessl, David

2009-01-01

Gaze avoidance is a hallmark behavioral feature of fragile X syndrome (FXS), but little is known about whether abnormalities in the visual processing of faces, including disrupted autonomic reactivity, may underlie this behavior. Eye tracking was used to record fixations and pupil diameter while adolescents and young adults with FXS and sex- and…

Early Temperament and Negative Reactivity in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Shanahan, M.; Roberts, J.; Hatton, D.; Reznick, J.; Goldsmith, H.

2008-01-01

Background: The phenotype of children and adults with fragile X syndrome (FXS) includes a number of problem behaviours such as inattention, social anxiety and aggressive outbursts. However, very little work has been conducted with young children with FXS less than 5 years of age to examine the developmental pathway of problem behaviours in this…

A Comparison of Pragmatic Language in Boys with Autism and Fragile X Syndrome

ERIC Educational Resources Information Center

Klusek, Jessica; Martin, Gary E.; Losh, Molly

2014-01-01

Purpose: Impaired pragmatic language (i.e., language use for social interaction) is a hallmark feature of both autism spectrum disorder (ASD) and fragile X syndrome (FXS), the most common known monogenic disorder associated with ASD. However, few cross-population comparisons of ASD and FXS have been conducted, and it is unclear whether pragmatic…

A "Learning Platform" Approach to Outcome Measurement in Fragile X Syndrome: A Preliminary Psychometric Study

ERIC Educational Resources Information Center

Hall, S. S.; Hammond, J. L.; Hirt, M.; Reiss, A. L.

2012-01-01

Background: Clinical trials of medications to alleviate the cognitive and behavioural symptoms of individuals with fragile X syndrome (FXS) are now underway. However, there are few reliable, valid and/or sensitive outcome measures available that can be directly administered to individuals with FXS. The majority of assessments employed in clinical…

The Longitudinal Effects of Parenting on Adaptive Behavior in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Warren, Steven F.; Brady, Nancy; Fleming, Kandace K.; Hahn, Laura J.

2017-01-01

Several studies have reported declines in adaptive behavior amongst children with fragile X syndrome (FXS) starting in middle childhood. We examined the effects of maternal responsivity on adaptive behavior in 55 children with FXS visited 5-6 times in their homes from early through middle childhood. Our analyses indicated that sustained maternal…

A Pilot Study of Social Information Processing Skills in Girls with Fragile X Syndrome

ERIC Educational Resources Information Center

Russo-Ponsaran, Nicole M.; Berry-Kravis, Elizabeth; McKown, Clark A.; Lipton, Meryl

2014-01-01

Fragile X syndrome (FXS) is a well-described inherited cause of intellectual disability and the most common known genetic cause of autism. Social deficits in girls with FXS are not well understood. To better understand barriers to social functioning that may contribute to mental health outcomes, we administered a theoretically based social…

Early Language Development in Infants and Toddlers with Fragile X Syndrome: Change over Time and the Role of Attention

PubMed Central

Kover, Sara T.; McCary, Lindsay M.; Ingram, Alexandra M.; Hatton, Deborah D.; Roberts, Jane E.

2017-01-01

Fragile X syndrome (FXS) is associated with significant language and communication delays, as well as problems with attention. This study investigated early language abilities in infants and toddlers with FXS (n = 13) and considered visual attention as a predictor of those skills. We found that language abilities increased over the study period of 9 to 24 months with moderate correlations among language assessments. In comparison to typically developing infants (n = 11), language skills were delayed beyond chronological age- and developmental level-expectations. Aspects of early visual attention predicted later language ability. Atypical visual attention is an important aspect of the FXS phenotype with implications for early language development, particularly in the domain of vocabulary. PMID:25715182

A comparison of functional academic and daily living skills in males with fragile X syndrome with and without autism.

PubMed

Raspa, Melissa; Franco, Vitor; Bishop, Ellen; Wheeler, Anne C; Wylie, Amanda; Bailey, Donald B

2018-05-03

Adaptive behaviors, such as functional academic and daily living skills, are critical for independence in adults with intellectual and developmental disabilities. However, little is known about these skills in fragile X syndrome (FXS), the most common form of inherited intellectual disability. The purposes of this study were to describe the functional academic and daily living skills of males diagnosed with FXS across different age groups and compare skill attainment by autism status and other common co-occurring conditions. We used survey methods to assess parent-reported functional academic and daily living skills in 534 males with FXS. Functional academic skills included time and schedules, money, math, reading, and writing skills. Daily living skills included hygiene, cooking, laundry and housekeeping, transportation, and safety skills. Analyses examined functional academic and daily living skills in a cross-sectional sample of males between ages 5 and 67. Differences in skill attainment were found by child age, co-morbid autism status, total number of co-occurring conditions, and respondent education. Functional academic and daily living skills were predictive of community employment and independent living. These data provide important information on the mastery of both foundational and more complex adaptive skills in males with FXS. Both functional academic and daily living skills were predictive of measures of independence above and beyond other child and family characteristics. These findings point to the need to focus interventions to support the attainment of independence in males with FXS. Copyright © 2018 Elsevier Ltd. All rights reserved.

Using Percentile Schedules to Increase Eye Contact in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hall, Scott S.; Maynes, Natalee P.; Reiss, Allan L.

2009-01-01

Aversion to eye contact is a common behavior of individuals diagnosed with Fragile X syndrome (FXS); however, no studies to date have attempted to increase eye-contact duration in these individuals. In this study, we employed a percentile reinforcement schedule with and without overcorrection to shape eye-contact duration of 6 boys with FXS.…

Investigating Word Learning in Fragile X Syndrome: A Fast-Mapping Study

ERIC Educational Resources Information Center

McDuffie, Andrea; Kover, Sara T.; Hagerman, Randi; Abbeduto, Leonard

2013-01-01

Fast-mapping paradigms have not been used previously to examine the process of word learning in boys with fragile X syndrome (FXS), who are likely to have intellectual impairment, language delays, and symptoms of autism. In this study, a fast-mapping task was used to investigate associative word learning in 4- to 10-year-old boys with FXS relative…

Psychometric Study of the Aberrant Behavior Checklist in Fragile X Syndrome and Implications for Targeted Treatment

ERIC Educational Resources Information Center

Sansone, Stephanie M.; Widaman, Keith F.; Hall, Scott S.; Reiss, Allan L.; Lightbody, Amy; Kaufmann, Walter E.; Berry-Kravis, Elizabeth; Lachiewicz, Ave; Brown, Elaine C.; Hessl, David

2012-01-01

Animal studies elucidating the neurobiology of fragile X syndrome (FXS) have led to multiple controlled trials in humans, with the Aberrant Behavior Checklist-Community (ABC-C) commonly adopted as a primary outcome measure. A multi-site collaboration examined the psychometric properties of the ABC-C in 630 individuals (ages 3-25) with FXS using…

Language Development in Infants and Toddlers with Fragile X Syndrome: Change over Time and the Role of Attention

ERIC Educational Resources Information Center

Kover, Sara T.; McCary, Lindsay M.; Ingram, Alexandra M.; Hatton, Deborah D.; Roberts, Jane E.

2015-01-01

Fragile X syndrome (FXS) is associated with significant language and communication delays, as well as problems with attention. This study investigated early language abilities in infants and toddlers with FXS (n = 13) and considered visual attention as a predictor of those skills. We found that language abilities increased over the study period of…

Parents' Decisions to Screen Their Newborn for Fragile X Syndrome. FPG Snapshot #63

ERIC Educational Resources Information Center

FPG Child Development Institute, 2011

2011-01-01

State newborn screening (NBS) programs have expanded in recent years, and more tests may be added in the future. The expansion of neonatal screening raises ethical, legal, and social questions. The questions surrounding NBS for fragile X syndrome (FXS) typify these concerns. FXS is an X-linked genetic condition that is the most common inherited…

Expressive Language Profiles of Verbally Expressive Adolescents and Young Adults with Down Syndrome or Fragile X Syndrome

ERIC Educational Resources Information Center

Finestack, Lizbeth H.; Abbeduto, Leonard

2010-01-01

Purpose: In this study, the authors examined the expressive language abilities of a subset of highly verbally expressive adolescents and young adults with Down syndrome (DS) and those with fragile X syndrome (FXS) for evidence of syndrome-related differences. FXS gender differences were also examined in an exploratory fashion. Method: The authors…

Behaviour Problems, Maternal Internalising Symptoms and Family Relations in Families of Adolescents and Adults with Fragile X Syndrome

ERIC Educational Resources Information Center

Baker, J. K.; Seltzer, M. M.; Greenberg, J. S.

2012-01-01

Background: Studies have linked the behaviour problems of children with fragile X syndrome (FXS) to maternal well-being, but less is known about how behaviour problems relate to important family factors such as marital satisfaction and family cohesion. Methods: Married mothers of 115 adolescents and adults with FXS completed questionnaires and…

DSM-5 Changes and the Prevalence of Parent-Reported Autism Spectrum Symptoms in Fragile X Syndrome

ERIC Educational Resources Information Center

Wheeler, Anne C.; Mussey, Joanna; Villagomez, Adrienne; Bishop, Ellen; Raspa, Melissa; Edwards, Anne; Bodfish, James; Bann, Carla; Bailey, Donald B.

2015-01-01

We used survey methodology to assess parent-reported autism symptomology in 758 individuals (639 males; 119 females) with fragile X syndrome (FXS). Caregivers reported whether their child with FXS had been diagnosed with an autism spectrum disorder (ASD) and endorsed symptoms based on a list of observable behaviors related to ASD diagnoses.…

The Relationship between Autistic Symptomatology and Independent Living Skills in Adolescents and Young Adults with Fragile X Syndrome

ERIC Educational Resources Information Center

Hustyi, Kristin M.; Hall, Scott S.; Quintin, Eve-Marie; Chromik, Lindsay C.; Lightbody, Amy A.; Reiss, Allan L.

2015-01-01

Few studies have examined the relationship between autistic symptomatology and competence in independent living skills in adolescents and young adults with fragile X syndrome (FXS). In this study, 70 individuals with FXS, aged 15-25 years, and 35 matched controls were administered direct measures of independent living skills and autistic…

Trajectories of Early Brain Volume Development in Fragile X Syndrome and Autism

ERIC Educational Resources Information Center

Hazlett, Heather Cody; Poe, Michele D.; Lightbody, Amy A.; Styner, Martin; MacFall, James R.; Reiss, Allan L.; Piven, Joseph

2012-01-01

Objective: To examine patterns of early brain growth in young children with fragile X syndrome (FXS) compared with a comparison group (controls) and a group with idiopathic autism. Method: The study included 53 boys 18 to 42 months of age with FXS, 68 boys with idiopathic autism (autism spectrum disorder), and a comparison group of 50 typically…

Consistency between Research and Clinical Diagnoses of Autism among Boys and Girls with Fragile X Syndrome

ERIC Educational Resources Information Center

Klusek, J.; Martin, G. E.; Losh, M.

2014-01-01

Background: Prior research suggests that 60-74% of males and 16-45% of females with fragile X syndrome (FXS) meet criteria for autism spectrum disorder (ASD) in research settings. However, relatively little is known about the rates of clinical diagnoses in FXS and whether such diagnoses are consistent with those performed in a research setting…

Theory of Mind Deficits in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Cornish, K.; Burack, J. A.; Rahman, A.; Munir, F.; Russo, N.; Grant, C.

2005-01-01

Given the consistent findings of theory of mind deficits in children with autism, it would be extremely beneficial to examine the profile of theory of mind abilities in other clinical groups such as fragile X syndrome (FXS) and Down syndrome (DS). The aim of the present study was to assess whether boys with FXS are impaired in simple social…

Topological methods reveal high and low functioning neuro-phenotypes within fragile X syndrome

PubMed Central

Romano, David; Nicolau, Monica; Quintin, Eve-Marie; Mazaika, Paul; Lightbody, Amy; Hazlett, Heather; Piven, Joseph; Carlsson, Gunnar; Reiss, Allan

2014-01-01

Fragile X syndrome (FXS), due to mutations of the FMR1 gene, is the most common known inherited cause of developmental disability as well as the most common single-gene risk factor for autism. Our goal was to examine variation in brain structure in FXS with topological data analysis (TDA), and to assess how such variation is associated with measures of IQ and autism-related behaviors. To this end, we analyzed imaging and behavioral data from young boys (n=52; aged 1.57-4.15 years) diagnosed with FXS. Application of topological methods to structural MRI data revealed two large subgroups within the study population. Comparison of these subgroups showed significant between-subgroup neuroanatomical differences similar to those previously reported to distinguish children with FXS from typically developing controls (e.g., enlarged caudate). In addition to neuroanatomy, the groups showed significant differences in IQ and autism severity scores. These results suggest that despite arising from a single gene mutation, fragile X syndrome may encompass two biologically and clinically separable phenotypes. In addition, these findings underscore the potential of TDA as a powerful tool in the search for biological phenotypes of neuropsychiatric disorders. PMID:24737721

Maternal Well-Being and Child Behavior in Families with Fragile X Syndrome

PubMed Central

Hauser, Claire T.; Kover, Sara T.; Abbeduto, Leonard

2014-01-01

The purpose of this study was to examine the bidirectional relationshipsnetres behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health disorders due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, child challenging behavior was related to changes in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the result regarding maternal closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research. PMID:24984053

Comparative study of laterality in people with fragile X syndrome, people with intellectual disabilities, and people with typical development.

PubMed

Niort, Jannick; Hernández Vázquez, Francisco Javier

2017-07-01

Following on from the studies by McManus and Cornish [(1997). Fractionating handedness in mental retardation: What is the role of the cerebellum? Laterality, 2(2), 81-89] and Cornish, Pigram, and Shaw [(1997). Do anomalies of handedness exist in children with fragile-X syndrome? Laterality, 2(2), 91-101], the aim of this paper was to determine laterality in people with fragile X syndrome (FXS). The sample comprised three study groups: the first with 30 people with FXS (mean age 17.9 years), the second 34 people with various intellectual disabilities (ID, mean age 20.9 years), and the third 160 people with typical development (mean age 14.7 years). Laterality was assessed with a test adapted for this study. The results confirm the preponderance of right-handedness (93.3%) in people with FXS and present new data regarding footedness and sensory dominance (eyedness and earedness), indicating inconsistent footedness and ocular cross-dominance. Almost three-quarters (73.5%) of people with other ID were right-handed. The results corroborate those of McManus and Cornish (1997). People with FXS tend to be right-handed but have ocular cross-dominance.

Bigger is better and worse: on the intricate relationship between hippocampal size and memory.

PubMed

Molnár, Katalin; Kéri, Szabolcs

2014-04-01

The structure-function relationship between the hippocampal region and memory is a debated topic in the literature. It has been suggested that larger hippocampi are associated with less effective memory performance in healthy young adults because of a partial synaptic pruning. Here, we tested this hypothesis in individuals with Fragile X Syndrome (FXS) with known abnormal pruning and IQ- and age-matched individuals with hypoxic brain injury, preterm birth, and obstetric complications. Results revealed larger normalized hippocampal volume in FXS compared with neurotypical controls, whereas individuals with hypoxic injury had smaller hippocampi. In neurotypical controls and individuals with hypoxic injury, better general memory, as indexed by the Wechsler Memory Scale-Revised, was associated with larger hippocampus. In contrast, in FXS we observed the opposite relationship: larger hippocampus was associated with worse general memory. Caudate volume did not correlate with memory in either group. These results suggest that incomplete pruning in young healthy adults may not contribute to less efficient memory capacity, and hippocampal size is positively associated with memory performance. However, abnormally large and poorly pruned hippocampus may indeed be less effective in FXS. Copyright © 2014 Elsevier Ltd. All rights reserved.

Interference of the complex between NCS-1 and Ric8a with phenothiazines regulates synaptic function and is an approach for fragile X syndrome.

PubMed

Mansilla, Alicia; Chaves-Sanjuan, Antonio; Campillo, Nuria E; Semelidou, Ourania; Martínez-González, Loreto; Infantes, Lourdes; González-Rubio, Juana María; Gil, Carmen; Conde, Santiago; Skoulakis, Efthimios M C; Ferrús, Alberto; Martínez, Ana; Sánchez-Barrena, María José

2017-02-07

The protein complex formed by the Ca 2+ sensor neuronal calcium sensor 1 (NCS-1) and the guanine exchange factor protein Ric8a coregulates synapse number and probability of neurotransmitter release, emerging as a potential therapeutic target for diseases affecting synapses, such as fragile X syndrome (FXS), the most common heritable autism disorder. Using crystallographic data and the virtual screening of a chemical library, we identified a set of heterocyclic small molecules as potential inhibitors of the NCS-1/Ric8a interaction. The aminophenothiazine FD44 interferes with NCS-1/Ric8a binding, and it restores normal synapse number and associative learning in a Drosophila FXS model. The synaptic effects elicited by FD44 feeding are consistent with the genetic manipulation of NCS-1. The crystal structure of NCS-1 bound to FD44 and the structure-function studies performed with structurally close analogs explain the FD44 specificity and the mechanism of inhibition, in which the small molecule stabilizes a mobile C-terminal helix inside a hydrophobic crevice of NCS-1 to impede Ric8a interaction. Our study shows the drugability of the NCS-1/Ric8a interface and uncovers a suitable region in NCS-1 for development of additional drugs of potential use on FXS and related synaptic disorders.

Autism Symptomatology in Boys with Fragile X Syndrome: A Cross Sectional Developmental Trajectories Comparison with Nonsyndromic Autism Spectrum Disorder

PubMed Central

Thurman, Angela John; McDuffie, Andrea; Kover, Sara T.; Hagerman, Randi J.; Abbeduto, Leonard

2015-01-01

Although males with fragile X syndrome (FXS) are frequently described as demonstrating autism symptomatology, there is much debate regarding whether the behavioral symptoms representing the core domains of autism are the result of the same or different underlying neurological/psychological mechanisms. The present study used a cross-sectional developmental trajectories approach to compare the profiles of autism symptomatology relative to chronological age (CA), nonverbal IQ, and expressive vocabulary ability between individuals with FXS and individuals with nonsyndromic ASD. Results suggest that the onset of autism symptoms and their developmental trajectories in males with FXS differ in important ways as a function of chronological age, nonverbal cognitive ability, and expressive vocabulary relative to males with nonsyndromic ASD. Theoretical and clinical implications are discussed. PMID:25904201

Use of Emotional Cues for Lexical Learning: A Comparison of Autism Spectrum Disorder and Fragile X Syndrome

PubMed Central

Thurman, Angela John; McDuffie, Andrea; Kover, Sara T.; Hagerman, Randi; Channell, Marie Moore; Mastergeorge, Ann; Abbeduto, Leonard

2014-01-01

The present study evaluated the ability of males with fragile X syndrome (FXS), nonsyndromic autism spectrum disorder (ASD), or typical development to learn new words by using as a cue to the intended referent an emotional reaction indicating a successful (excitement) or unsuccessful (disappointment) search for a novel object. Performance for all groups exceeded chance-levels in both search conditions. In the Successful Search condition, participants with nonsyndromic ASD performed similarly to participants with FXS after controlling for severity of ASD. In the Unsuccessful Search condition, participants with FXS performed significantly worse than participants with nonsyndromic ASD, after controlling for severity of ASD. Predictors of performance in both search conditions differed between the three groups. Theoretical and clinical implications are discussed. PMID:25318904

Differential Relationships of Anxiety and Autism Symptoms on Social Skills in Young Boys With Fragile X Syndrome.

PubMed

Reisinger, Debra L; Roberts, Jane E

2017-09-01

Social skills are critical for academic, social, and psychological success of children with both typical and atypical development. Boys with fragile X syndrome (FXS) are at high risk for social skill impairments, given intellectual impairments and secondary conditions. The present study examines the impact of adaptive behavior, autism symptoms, and anxiety symptoms to social skills at the composite and subdomain level in boys with FXS across age. This cross-sectional study included boys with FXS (3-14 years) contrasted to age-matched typical control boys. Results revealed that social skills are generally within developmental expectations, with adaptive behavior as the primary predictor. Anxiety and autism symptoms emerged as additive risk factors, particularly in the areas of responsibility and self-control.

GABA-B Agonist Baclofen Normalizes Auditory-Evoked Neural Oscillations and Behavioral Deficits in the Fmr1 Knockout Mouse Model of Fragile X Syndrome

PubMed Central

Featherstone, R.; Naschek, M.; Nam, J.; Du, A.; Wright, S.; Weger, R.; Akuzawa, S.

2017-01-01

Abstract Fragile X syndrome is a genetic condition resulting from FMR1 gene mutation that leads to intellectual disability, autism-like symptoms, and sensory hypersensitivity. Arbaclofen, a GABA-B agonist, has shown efficacy in some individuals with FXS but has become unavailable after unsuccessful clinical trials, prompting interest in publicly available, racemic baclofen. The present study investigated whether racemic baclofen can remediate abnormalities of neural circuit function, sensory processing, and behavior in Fmr1 knockout mice, a rodent model of fragile X syndrome. Fmr1 knockout mice showed increased baseline and auditory-evoked high-frequency gamma (30–80 Hz) power relative to C57BL/6 controls, as measured by electroencephalography. These deficits were accompanied by decreased T maze spontaneous alternation, decreased social interactions, and increased open field center time, suggestive of diminished working memory, sociability, and anxiety-like behavior, respectively. Abnormal auditory-evoked gamma oscillations, working memory, and anxiety-related behavior were normalized by treatment with baclofen, but impaired sociability was not. Improvements in working memory were evident predominantly in mice whose auditory-evoked gamma oscillations were dampened by baclofen. These findings suggest that racemic baclofen may be useful for targeting sensory and cognitive disturbances in fragile X syndrome. PMID:28451631

Multifarious Functions of the Fragile X Mental Retardation Protein.

PubMed

Davis, Jenna K; Broadie, Kendal

2017-10-01

Fragile X syndrome (FXS), a heritable intellectual and autism spectrum disorder (ASD), results from the loss of Fragile X mental retardation protein (FMRP). This neurodevelopmental disease state exhibits neural circuit hyperconnectivity and hyperexcitability. Canonically, FMRP functions as an mRNA-binding translation suppressor, but recent findings have enormously expanded its proposed roles. Although connections between burgeoning FMRP functions remain unknown, recent advances have extended understanding of its involvement in RNA, channel, and protein binding that modulate calcium signaling, activity-dependent critical period development, and the excitation-inhibition (E/I) neural circuitry balance. In this review, we contextualize 3 years of FXS model research. Future directions extrapolated from recent advances focus on discovering links between FMRP roles to determine whether FMRP has a multitude of unrelated functions or whether combinatorial mechanisms can explain its multifaceted existence. Copyright © 2017 Elsevier Ltd. All rights reserved.

Symptoms of Autism in Males with Fragile X Syndrome: A Comparison to Nonsyndromic ASD Using Current ADI-R Scores

ERIC Educational Resources Information Center

McDuffie, Andrea; Thurman, Angela John; Hagerman, Randi J.; Abbeduto, Leonard

2015-01-01

Symptoms of autism are frequent in males with fragile X syndrome (FXS), but it is not clear whether symptom profiles differ from those of nonsyndromic ASD. Using individual item scores from the Autism Diagnostic Inventory-Revised, we examined which current symptoms of autism differed in boys with FXS relative to same-aged boys diagnosed with…

Using Discrete Trial Training to Identify Specific Learning Impairments in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Hall, Scott S.; Hustyi, Kristin M.; Hammond, Jennifer L.; Hirt, Melissa; Reiss, Allan L.

2014-01-01

We examined whether "discrete trial training" (DTT) could be used to identify learning impairments in mathematical reasoning in boys with fragile X syndrome (FXS). Boys with FXS, aged 10-23 years, and age and IQ-matched controls, were trained to match fractions to pie-charts and pie-charts to decimals either on a computer or with a…

Autism Spectrum Disorder Symptoms in Infants with Fragile X Syndrome: A Prospective Case Series

ERIC Educational Resources Information Center

Hogan, Abigail L.; Caravella, Kelly E.; Ezell, Jordan; Rague, Lisa; Hills, Kimberly; Roberts, Jane E.

2017-01-01

No studies to date have prospectively examined early autism spectrum disorder (ASD) markers in infants with fragile X syndrome (FXS), who are at elevated risk for ASD. This paper describes the developmental profiles of eight infants with FXS from 9 to 24 months of age. Four meet diagnostic criteria for ASD at 24 months of age, and four do not.…

Importance of a specialty clinic for individuals with fragile X syndrome.

PubMed

Visootsak, Jeannie; Kidd, Sharon A; Anderson, Tovi; Bassell, Julia L; Sherman, Stephanie L; Berry-Kravis, Elizabeth M

2016-12-01

Advances in human genetics have identified a significant number of genetic disorders associated with intellectual disability. As a result, appropriate clinical management of these affected individuals and their family members have become critical in addressing medical needs to improve quality of life. We examine the importance of a Fragile X Clinic for individuals with fragile X syndrome (FXS) and their family members by conducting a retrospective chart review of 123 new patients with FXS evaluated at the Fragile X Clinic at Emory University. After the initial diagnosis of a proband with FXS with cascade testing, there were 345 family members identified with a mutation (70% with premutations; 30% with full mutations). In terms of the impact of the clinic visit, males had a substantial number of new diagnoses in all behavioral disorders (P < 0.001), with anxiety (62%) being the most common. For female probands, the most frequent diagnosis was also anxiety (87%). Prior to the clinic visit, very few patients were prescribed psychotropic medications. After the clinic visit, the most frequently prescribed psychotropic medications for males were stimulants (41%; P < 0.001) and SSRIs (40%; P < 0.001). For females, only stimulants (33%; P = 0.03) and SSRIs (44%; P = 0.008) were statistically significantly prescribed. Our results revealed that there is a gap in care to address the co-morbid behavioral issues, psychopharmacologic medication management, and genetic counseling needs regarding FXS. A multidisciplinary setting and approach, such as that offered by a Fragile X Clinic, is one method of treating the complex needs of patients with FXS. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

The Efficacy of Melatonin for Sleep Problems in Children with Autism, Fragile X Syndrome, or Autism and Fragile X Syndrome

PubMed Central

Wirojanan, Juthamas; Jacquemont, Sebastien; Diaz, Rafael; Bacalman, Susan; Anders, Thomas F.; Hagerman, Randi J.; Goodlin-Jones, Beth L.

2009-01-01

Study Objective: To determine the efficacy of melatonin on sleep problems in children with autistic spectrum disorder (ASD) and fragile X syndrome (FXS). Methods: A 4-week, randomized, double blind, placebo-controlled, crossover design was conducted following a 1-week baseline period. Either melatonin, 3 mg, or placebo was given to participants for 2 weeks and then alternated for another 2 weeks. Sleep variables, including sleep duration, sleep-onset time, sleep-onset latency time, and the number of night awakenings, were recorded using an Actiwatch and from sleep diaries completed by parents. All participants had been thoroughly assessed for ASD and also had DNA testing for the diagnosis of FXS. Results: Data were successfully obtained from the 12 of 18 subjects who completed the study (11 males, age range 2 to 15.25 years, mean 5.47, SD 3.6). Five participants met diagnostic criteria for ASD, 3 for FXS alone, 3 for FXS and ASD, and 1 for fragile X premutation. Eight out of 12 had melatonin first. The conclusions from a nonparametric repeated-measures technique indicate that mean night sleep duration was longer on melatonin than placebo by 21 minutes (p = .02), mean sleep-onset latency was shorter by 28 minutes (p = .0001), and mean sleep-onset time was earlier by 42 minutes (p = .02). Conclusion: The results of this study support the efficacy and tolerability of melatonin treatment for sleep problems in children with ASD and FXS. Citation: Wirojanan J; Jacquemont S; Diaz R; Bacalman S; Anders TF; Hagerman RJ; Goodlin-Jones BL. The Efficacy of Melatonin for Sleep Problems in Children with Autism, Fragile X Syndrome, or Autism and Fragile X Syndrome. J Clin Sleep Med 2009;5(2):145-150. PMID:19968048

Evaluating Sensory Processing in Fragile X Syndrome: Psychometric Analysis of the Brain Body Center Sensory Scales (BBCSS).

PubMed

Kolacz, Jacek; Raspa, Melissa; Heilman, Keri J; Porges, Stephen W

2018-06-01

Individuals with fragile X syndrome (FXS), especially those co-diagnosed with autism spectrum disorder (ASD), face many sensory processing challenges. However, sensory processing measures informed by neurophysiology are lacking. This paper describes the development and psychometric properties of a parent/caregiver report, the Brain-Body Center Sensory Scales (BBCSS), based on Polyvagal Theory. Parents/guardians reported on 333 individuals with FXS, 41% with ASD features. Factor structure using a split-sample exploratory-confirmatory design conformed to neurophysiological predictions. Internal consistency, test-retest, and inter-rater reliability were good to excellent. BBCSS subscales converged with the Sensory Profile and Sensory Experiences Questionnaire. However, data also suggest that BBCSS subscales reflect unique features related to sensory processing. Individuals with FXS and ASD features displayed more sensory challenges on most subscales.

Modeling Family Dynamics in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hall, Scott S.; Burns, David D.; Reiss, Allan L.

2007-01-01

Few studies have examined the impact of children with genetic disorders and their unaffected siblings on family functioning. In this study, the reciprocal causal links between problem behaviors and maternal distress were investigated in 150 families containing a child with fragile X syndrome (FXS) and an unaffected sibling. Both children's…

Employment Impact and Financial Burden for Families of Children with Fragile X Syndrome: Findings from the National Fragile X Survey

ERIC Educational Resources Information Center

Ouyang, L.; Grosse, S.; Raspa, M.; Bailey, D.

2010-01-01

Background: The employment impact and financial burden experienced by families of children with fragile X syndrome (FXS) has not been quantified in the USA. Method: Using a national fragile X family survey, we analysed data on 1019 families with at least one child who had a full FXS mutation. Out-of-pocket expenditures related to fragile X were…

Maternal well-being and child behavior in families with fragile X syndrome.

PubMed

Hauser, Claire T; Kover, Sara T; Abbeduto, Leonard

2014-10-01

The purpose of this study was to examine the bidirectional relationships relationship between maternal mental health status, maternal stress, family environment and behavioral functioning of children with fragile X syndrome (FXS), the leading cause of inherited intellectual disability. Children with FXS commonly demonstrate challenging behavior related to anxiety, attention, and aggression, whereas mothers of children with FXS have been identified as susceptible to mental health challenges due to their status as genetic carriers of the FXS premutation, as well as the environmental stressors of raising children with special needs. The longitudinal design of this study builds upon prior work that established a concurrent relationship among these factors in families of children with other intellectual disorders. Findings indicated that maternal mental health status was not significantly related to changes in levels of child challenging behavior, heightened child challenging behavior was related to improvements in maternal depression over time, and heightened levels of child challenging behavior was related to increased feelings of maternal closeness toward the child over time. The unexpected nature of the results regarding maternal depression and closeness provides new and more complex hypotheses about how mothers of special needs children demonstrate adaptation and resilience. The findings have implications for maternal and familial mental health treatment as well as future research. Copyright © 2014 Elsevier Ltd. All rights reserved.

Role of Altered mGluR Activity in Cognitive Impairments in TSC: Implications for a Novel Method of Treatment

DTIC Science & Technology

2013-04-01

epilepsy, autism , anxiety and mood disorders. Fragile X syndrome (FXS), another form of inherited mental retardation and autism , shares many of the...therapeutic intervention for several of the deficits observed in TSC. 15. SUBJECT TERMS autism , Tuberous Sclerosis Complex, Fragile X Syndrome...clinical features being mental retardation, epilepsy, autism , anxiety and mood disorders (Prather & de Vries, 2004). Fragile X syndrome (FXS

Molecular mechanisms of fragile X syndrome: a twenty-year perspective.

PubMed

Santoro, Michael R; Bray, Steven M; Warren, Stephen T

2012-01-01

Fragile X syndrome (FXS) is a common form of inherited intellectual disability and is one of the leading known causes of autism. The mutation responsible for FXS is a large expansion of the trinucleotide CGG repeat in the 5' untranslated region of the X-linked gene FMR1. This expansion leads to DNA methylation of FMR1 and to transcriptional silencing, which results in the absence of the gene product, FMRP, a selective messenger RNA (mRNA)-binding protein that regulates the translation of a subset of dendritic mRNAs. FMRP is critical for mGluR (metabotropic glutamate receptor)-dependent long-term depression, as well as for other forms of synaptic plasticity; its absence causes excessive and persistent protein synthesis in postsynaptic dendrites and dysregulated synaptic function. Studies continue to refine our understanding of FMRP's role in synaptic plasticity and to uncover new functions of this protein, which have illuminated therapeutic approaches for FXS.

Associating Neural Alterations and Genotype in Autism and Fragile X Syndrome: Incorporating Perceptual Phenotypes in Causal Modeling

ERIC Educational Resources Information Center

Bertone, Armando; Hanck, Julie; Kogan, Cary; Chaudhuri, Avi; Cornish, Kim

2010-01-01

We have previously described (see companion paper, this issue) the utility of using perceptual signatures for defining and dissociating condition-specific neural functioning underlying early visual processes in autism and FXS. These perceptually-driven hypotheses are based on differential performance evidenced only at the earliest stages of visual…

A Preliminary Study of Screening for Risk of Autism in Children with Fragile X Syndrome: Testing Two Risk Cut-Offs for the Checklist for Autism in Toddlers

ERIC Educational Resources Information Center

Scambler, D. J.; Hepburn, S. L.; Hagerman, R. J.; Rogers, S. J.

2007-01-01

Objective: Risk criteria for the Checklist for Autism in Toddlers (CHAT) and modified risk criteria (i.e. the Denver Criteria) were compared in a group of children with fragile X syndrome (FXS) and autism. Method: Participants were 17 children aged 2-4 years with DNA confirmation of FXS. Four children had autism and 13 children did not. Results:…

Autism, Alzheimer disease, and fragile X

PubMed Central

Sokol, D.K.; Maloney, B.; Long, J.M.; Ray, B.

2011-01-01

The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-β peptide (Aβ), Aβ precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-β precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell–cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aβ would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism. PMID:21482951

Social/economic costs and health-related quality of life in patients with fragile X syndrome in Europe.

PubMed

Chevreul, Karine; Gandré, Coralie; Brigham, Karen Berg; López-Bastida, Julio; Linertová, Renata; Oliva-Moreno, Juan; Serrano-Aguilar, Pedro; Posada-de-la-Paz, Manuel; Taruscio, Domenica; Schieppati, Arrigo; Iskrov, Georgi; Gulácsi, László; von der Schulenburg, Johann Matthias Graf; Kanavos, Panos; Persson, Ulf; Fattore, Giovani

2016-04-01

To estimate the social/economic costs of fragile X syndrome (FXS) in Europe and to assess the health-related quality of life (HRQOL) of patients and caregivers. A cross-sectional study was conducted in a sample of European countries. Patients were recruited through patients' associations. Data on their resource use and absence from the labour market were retrospectively obtained from an online questionnaire. Costs were estimated by a bottom-up approach and the EuroQol-5 Domain (EQ-5D) questionnaire was used to measure patients' and caregivers' HRQOL. Five countries were included in the analysis. The mean annual cost of FXS per patient varied from €4951 in Hungary to €58,862 in Sweden. Direct non-healthcare costs represented the majority of costs in all countries but there were differences in the share incurred by formal and informal care among those costs. Costs were also shown to differ between children and adults. Mean EQ-5D utility score for adult patients varied from 0.52 in France (n = 42) to 0.73 in Hungary (n = 2), while for caregivers this score was consistently inferior to 0.87. Our findings underline that, although its prevalence is low, FXS is costly from a societal perspective. They support the development of tailored policies to reduce the consequences of FXS on both patients and their relatives.

Role of Altered mGluR Activity in Cognitive Impairments in TSC: Implications for a Novel Method of Treatment

DTIC Science & Technology

2012-04-01

defining factor. The most common clinical features are mental retardation, epilepsy, autism , anxiety and mood disorders. Fragile X syndrome (FXS...another form of inherited mental retardation and autism , shares many of the same molecular and clinical features as TSC. Much of the pathophysiology in FXS...modulation of mGluR activity with PAMs may serve as a therapeutic intervention for the treatment of TSC. 15. SUBJECT TERMS autism , Tuberous Sclerosis

Using Perceptual Signatures to Define and Dissociate Condition-Specific Neural Etiology: Autism and Fragile X Syndrome as Model Conditions

ERIC Educational Resources Information Center

Bertone, Armando; Hanck, Julie; Kogan, Cary; Chaudhuri, Avi; Cornish, Kim

2010-01-01

The functional link between genetic alteration and behavioral end-state is rarely straightforward and never linear. Cases where neurodevlopmental conditions defined by a distinct genetic etiology share behavioral phenotypes are exemplary, as is the case for autism and Fragile X Syndrome (FXS). In this paper and its companion paper, we propose a…

Longitudinal Changes in Intellectual Development in Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Hall, Scott S.; Burns, David D.; Lightbody, Amy A.; Reiss, Allan L.

2008-01-01

Structural equation modeling (SEM) was used to examine the development of intellectual functioning in 145 school-age pairs of siblings. Each pair included one child with Fragile X syndrome (FXS) and one unaffected sibling. All pairs of children were evaluated on the Wechsler Intelligence Scale for Children-Third Edition (WISC-III) at time 1 and 80…

Finding FMR1 mosaicism in Fragile X syndrome

PubMed Central

Gonçalves, Thaís Fernandez; dos Santos, Jussara Mendonça; Gonçalves, Andressa Pereira; Tassone, Flora; Mendoza-Morales, Guadalupe; Ribeiro, Márcia Gonçalves; Kahn, Evelyn; Boy, Raquel; Pimentel, Márcia Mattos Gonçalves; Santos-Rebouças, Cíntia Barros

2016-01-01

OBJETIVE Almost all patients with Fragile X Syndrome (FXS) exhibit a CGG repeat expansion (full mutation) in the Fragile Mental Retardation 1 gene (FMR1). Here, we report five unrelated males with FXS harboring a somatic full mutation/deletion mosaicism. METHODS Mutational profiles were only elucidated by using a combination of molecular approaches (CGG-based PCR, Sanger sequencing, MS-MLPA, Southern blot and mPCR). RESULT Four patients exhibited small deletions encompassing the CGG repeats tract and flanking regions, whereas the remaining had a larger deletion comprising at least exon 1 and part of intron 1 of FMR1 gene. The presence of a 2–3 base pairs microhomology in proximal and distal non-recurrent breakpoints without scars supports the involvement of microhomology mediated induced repair (MMBIR) mechanism in three small deletions. CONCLUSION Our data highlights the importance of using different research methods to elucidate atypical FXS mutational profiles, which are clinically undistinguishable and may have been underestimated. PMID:26716517

Altered Neuronal and Circuit Excitability in Fragile X Syndrome.

PubMed

Contractor, Anis; Klyachko, Vitaly A; Portera-Cailliau, Carlos

2015-08-19

Fragile X syndrome (FXS) results from a genetic mutation in a single gene yet produces a phenotypically complex disorder with a range of neurological and psychiatric problems. Efforts to decipher how perturbations in signaling pathways lead to the myriad alterations in synaptic and cellular functions have provided insights into the molecular underpinnings of this disorder. From this large body of data, the theme of circuit hyperexcitability has emerged as a potential explanation for many of the neurological and psychiatric symptoms in FXS. The mechanisms for hyperexcitability range from alterations in the expression or activity of ion channels to changes in neurotransmitters and receptors. Contributions of these processes are often brain region and cell type specific, resulting in complex effects on circuit function that manifest as altered excitability. Here, we review the current state of knowledge of the molecular, synaptic, and circuit-level mechanisms underlying hyperexcitability and their contributions to the FXS phenotypes. Copyright © 2015 Elsevier Inc. All rights reserved.

Examining the influence of social-environmental variables on self-injurious behaviour in adolescent boys with fragile X syndrome.

PubMed

Hall, S S; Hustyi, K M; Barnett, R P

2018-04-25

Individuals with fragile X syndrome (FXS), the most common known inherited form of intellectual disability, are at increased risk for showing specific forms of self-injurious behaviour (SIB) such as hand biting and head hitting, suggesting that biological factors associated with the syndrome confers increased risk for SIB. Few studies, however, have examined the extent to which social-environmental variables can influence the occurrence of these behaviours in this population. Twenty-two adolescent boys with FXS, aged 10 to 18 years were systematically exposed to seven environmental conditions in functional analyses of SIB conducted over 2 days at our research centre. Fourteen (63.6%) boys with FXS engaged in SIB during the functional analyses. Ten (45.5%) boys engaged in SIB that was maintained by social-environmental variables, that is, gaining access to attention/tangibles and/or escaping from social interaction, task demands and/or transition demands. For two boys, SIB was undifferentiated across conditions, and for two boys, SIB appeared to be maintained by automatic reinforcement. Social-environmental variables appeared to maintain SIB in a significant proportion of boys with FXS. Given that pharmacological treatments for SIB have limited efficacy in this population, the potential role of social-environmental factors on SIB should be examined before pharmacological treatments are implemented for these behaviours. © 2018 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Partially methylated alleles, microdeletion, and tissue mosaicism in a fragile X male with tremor and ataxia at 30 years of age: A case report.

PubMed

Hwang, Yun Tae; Aliaga, Solange Mabel; Arpone, Marta; Francis, David; Li, Xin; Chong, Belinda; Slater, Howard Robert; Rogers, Carolyn; Bretherton, Lesley; Hunter, Matthew; Heard, Robert; Godler, David Eugeny

2016-12-01

CGG repeat expansion >200 within FMR1, termed full mutation (FM), has been associated with promoter methylation, consequent silencing of gene expression and fragile X syndrome (FXS)-a common cause of intellectual disability and co-morbid autism. Unmethylated premutation (55-199 repeats) and FM alleles have been associated with fragile X related tremor/ataxia syndrome (FXTAS), a late onset neurodegenerative disorder. Here we present a 33-year-old male with FXS, with white matter changes and progressive deterioration in gait with cerebellar signs consistent with probable FXTAS; there was no evidence of any other cerebellar pathology. We show that he has tissue mosaicism in blood, saliva, and buccal samples for the size and methylation of his expanded alleles and a de novo, unmethylated microdeletion. This microdeletion involves a ∼80 bp sequence in the FMR1 promoter as well as complete loss of the CGG repeat in a proportion of cells. Despite FMR1 mRNA levels in blood within the normal range, the methylation and CGG sizing results are consistent with the diagnosis of concurrent FXS and probable FXTAS. The demonstrated presence of unmethylated FM alleles would explain the manifestation of milder than expected cognitive and behavioral impairments and early onset of cerebellar ataxia. Our case suggests that individuals with FXS, who manifest symptoms of FXTAS, may benefit from more detailed laboratory testing. © 2016 Wiley Periodicals, Inc. © 2016 Wiley Periodicals, Inc.

Effects of intranasal oxytocin on social anxiety in males with fragile X syndrome.

PubMed

Hall, Scott S; Lightbody, Amy A; McCarthy, Brigid E; Parker, Karen J; Reiss, Allan L

2012-04-01

Fragile X syndrome (FXS) is a rare inherited genetic disorder causing severe intellectual disability and autistic-like symptoms. Individuals with FXS, males in particular, often exhibit extreme eye gaze avoidance and hyperarousal when they encounter stressful social situations. We investigated whether oxytocin (OT), a hormone with prosocial and anxiolytic effects, could alleviate symptoms of social anxiety in this population. A randomized double-blind placebo-controlled single-dose trial was performed with intranasal administration of placebo, 24 IU OT and 48 IU OT. Measures of eye gaze frequency, heart rate, respiratory sinus arrhythmia (RSA), heart rate variability (HRV) and salivary cortisol were obtained during a structured social challenge conducted 50 min following OT administration. Ten low-functioning males with FXS (aged 13-28 years) traveled to Stanford for the initial visit: 8 completed the study. Eye gaze frequency improved significantly in response to the 24 IU OT dose and salivary cortisol levels decreased significantly in response to the 48 IU OT dose. There was no effect of OT on heart rate, RSA or HRV although individual plots of the heart rate data suggested that OT increased heart rate in some participants and decreased heart rate in others. These findings suggest that intranasal administration of OT may ameliorate some symptoms of social anxiety in patients with FXS. Further double-blind placebo-controlled studies of OT, conducted in combination with behavioral treatment programs, may be warranted. Copyright © 2011 Elsevier Ltd. All rights reserved.

Aggression in fragile X syndrome.

PubMed

Wheeler, A C; Raspa, M; Bishop, E; Bailey, D B

2016-02-01

Individuals with fragile X syndrome (FXS), especially men, have long been described as presenting with significant behavioural challenges. Despite this known aspect of the phenotype, there has been little research exploring the prevalence, frequency, nature or consequences of aggressive behaviour in FXS. This study used survey methodology to gather caregiver reports on the types, frequency and severity of aggressive behaviour in 774 individuals with FXS. Based on caregiver report, nearly all (>90%) male and female individuals were reported to have engaged in some aggression over the previous 12 months, with a third of male cases and slightly fewer than 20% of female cases being described as engaging in moderate to severe aggression or being diagnosed or treated for aggression. Further, aggressive behaviours in male individuals were serious enough that 30% had caused injuries to caregivers and 22% had caused injuries to peers or friends. Sensory issues and hyperactivity were significant predictors of the frequency of aggressive acts, while sensory issues and anxiety were predictive of the severity of aggression. Traditional behaviour management techniques as well as medication was described as the most common and successful treatment options. Aggressive behaviours are a significant concern for a subsample of both male and female individuals with FXS. Given that sensory concerns were predictive of both the frequency and the severity of aggression suggests these behaviours may be a reactive means of escaping uncomfortable situations. © 2015 MENCAP and International Association of the Scientific Study of Intellectual and Developmental Disabilities and John Wiley & Sons Ltd.

Autism, Alzheimer disease, and fragile X: APP, FMRP, and mGluR5 are molecular links.

PubMed

Sokol, D K; Maloney, B; Long, J M; Ray, B; Lahiri, D K

2011-04-12

The present review highlights an association between autism, Alzheimer disease (AD), and fragile X syndrome (FXS). We propose a conceptual framework involving the amyloid-β peptide (Aβ), Aβ precursor protein (APP), and fragile X mental retardation protein (FMRP) based on experimental evidence. The anabolic (growth-promoting) effect of the secreted α form of the amyloid-β precursor protein (sAPPα) may contribute to the state of brain overgrowth implicated in autism and FXS. Our previous report demonstrated that higher plasma sAPPα levels associate with more severe symptoms of autism, including aggression. This molecular effect could contribute to intellectual disability due to repression of cell-cell adhesion, promotion of dense, long, thin dendritic spines, and the potential for disorganized brain structure as a result of disrupted neurogenesis and migration. At the molecular level, APP and FMRP are linked via the metabotropic glutamate receptor 5 (mGluR5). Specifically, mGluR5 activation releases FMRP repression of APP mRNA translation and stimulates sAPP secretion. The relatively lower sAPPα level in AD may contribute to AD symptoms that significantly contrast with those of FXS and autism. Low sAPPα and production of insoluble Aβ would favor a degenerative process, with the brain atrophy seen in AD. Treatment with mGluR antagonists may help repress APP mRNA translation and reduce secretion of sAPP in FXS and perhaps autism.

Exaggerated Cap-Dependent Translation as a Mechanism for Corticostriatal Dysfunction in Fragile X Syndrome Model Mice

DTIC Science & Technology

2017-11-01

AWARD NUMBER: W81XWH-15-1-0361 TITLE: “Exaggerated Cap- Dependent Translation as a Mechanism for Corticostriatal Dysfunction in Fragile X...Annual 3. DATES COVERED 19Oct2016 - 18Oct2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER “Exaggerated Cap- Dependent Translation as a Mechanism for...altered cortico-striatal synaptic plasticity and repetitive/perseverative behaviors displayed by FXS model mice are reversed by novel cap- dependent

The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice.

PubMed

Bausch, Anne E; Dieter, Rebekka; Nann, Yvette; Hausmann, Mario; Meyerdierks, Nora; Kaczmarek, Leonard K; Ruth, Peter; Lukowski, Robert

2015-07-01

Kcnt1 encoded sodium-activated potassium channels (Slack channels) are highly expressed throughout the brain where they modulate the firing patterns and general excitability of many types of neurons. Increasing evidence suggests that Slack channels may be important for higher brain functions such as cognition and normal intellectual development. In particular, recent findings have shown that human Slack mutations produce very severe intellectual disability and that Slack channels interact directly with the Fragile X mental retardation protein (FMRP), a protein that when missing or mutated results in Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism in humans. We have now analyzed a recently developed Kcnt1 null mouse model in several behavioral tasks to assess which aspects of memory and learning are dependent on Slack. We demonstrate that Slack deficiency results in mildly altered general locomotor activity, but normal working memory, reference memory, as well as cerebellar control of motor functions. In contrast, we find that Slack channels are required for cognitive flexibility, including reversal learning processes and the ability to adapt quickly to unfamiliar situations and environments. Our data reveal that hippocampal-dependent spatial learning capabilities require the proper function of Slack channels. © 2015 Bausch et al.; Published by Cold Spring Harbor Laboratory Press.

The sodium-activated potassium channel Slack is required for optimal cognitive flexibility in mice

PubMed Central

Bausch, Anne E.; Dieter, Rebekka; Nann, Yvette; Hausmann, Mario; Meyerdierks, Nora; Kaczmarek, Leonard K.

2015-01-01

Kcnt1 encoded sodium-activated potassium channels (Slack channels) are highly expressed throughout the brain where they modulate the firing patterns and general excitability of many types of neurons. Increasing evidence suggests that Slack channels may be important for higher brain functions such as cognition and normal intellectual development. In particular, recent findings have shown that human Slack mutations produce very severe intellectual disability and that Slack channels interact directly with the Fragile X mental retardation protein (FMRP), a protein that when missing or mutated results in Fragile X syndrome (FXS), the most common form of inherited intellectual disability and autism in humans. We have now analyzed a recently developed Kcnt1 null mouse model in several behavioral tasks to assess which aspects of memory and learning are dependent on Slack. We demonstrate that Slack deficiency results in mildly altered general locomotor activity, but normal working memory, reference memory, as well as cerebellar control of motor functions. In contrast, we find that Slack channels are required for cognitive flexibility, including reversal learning processes and the ability to adapt quickly to unfamiliar situations and environments. Our data reveal that hippocampal-dependent spatial learning capabilities require the proper function of Slack channels. PMID:26077685

Metabotropic glutamate receptor-mediated use-dependent down-regulation of synaptic excitability involves the fragile X mental retardation protein.

PubMed

Repicky, Sarah; Broadie, Kendal

2009-02-01

Loss of the mRNA-binding protein FMRP results in the most common inherited form of both mental retardation and autism spectrum disorders: fragile X syndrome (FXS). The leading FXS hypothesis proposes that metabotropic glutamate receptor (mGluR) signaling at the synapse controls FMRP function in the regulation of local protein translation to modulate synaptic transmission strength. In this study, we use the Drosophila FXS disease model to test the relationship between Drosophila FMRP (dFMRP) and the sole Drosophila mGluR (dmGluRA) in regulation of synaptic function, using two-electrode voltage-clamp recording at the glutamatergic neuromuscular junction (NMJ). Null dmGluRA mutants show minimal changes in basal synapse properties but pronounced defects during sustained high-frequency stimulation (HFS). The double null dfmr1;dmGluRA mutant shows repression of enhanced augmentation and delayed onset of premature long-term facilitation (LTF) and strongly reduces grossly elevated post-tetanic potentiation (PTP) phenotypes present in dmGluRA-null animals. Null dfmr1 mutants show features of synaptic hyperexcitability, including multiple transmission events in response to a single stimulus and cyclic modulation of transmission amplitude during prolonged HFS. The double null dfmr1;dmGluRA mutant shows amelioration of these defects but does not fully restore wildtype properties in dfmr1-null animals. These data suggest that dmGluRA functions in a negative feedback loop in which excess glutamate released during high-frequency transmission binds the glutamate receptor to dampen synaptic excitability, and dFMRP functions to suppress the translation of proteins regulating this synaptic excitability. Removal of the translational regulator partially compensates for loss of the receptor and, similarly, loss of the receptor weakly compensates for loss of the translational regulator.

Cardiac Autonomic Regulation in Autism and Fragile X Syndrome: A Review

PubMed Central

Klusek, Jessica; Roberts, Jane E.; Losh, Molly

2014-01-01

Despite the significance of efforts to understand the biological basis of autism, progress in this area has been hindered, in part, by the considerable heterogeneity in the disorder. Fragile X syndrome (FXS), a monogenic condition associated with high risk for autism, may pave the way for the dissection of biological heterogeneity within idiopathic autism. This paper adopts a cross-syndrome biomarker approach to evaluate potentially overlapping profiles of cardiac arousal dysregulation (and broader autonomic dysfunction) in autism and FXS. Approaches such as this, aimed at delineating shared mechanisms across genetic syndromes, hold great potential for improving diagnostic precision, promoting earlier identification, and uncovering key systems that can be targeted in pharmaceutical/behavioral interventions. Biomarker approaches may be vital to deconstructing complex psychiatric disorders, and are currently promoted as such by major research initiatives such as the NIMH Research Domain Criteria (RDoC). Evidence reviewed here supports physiological dysregulation in a subset of individuals with autism, as evidenced by patterns of hyperarousal and dampened parasympathetic vagal tone, which overlap with the well-documented physiological profile of FXS. Moreover, there is growing support for a link between aberrant cardiac activity and core deficits associated with autism, such as communication and social impairment. The delineation of physiological mechanisms common to autism and FXS could lend insight into relationships between genetic etiology and behavioral endstates, highlighting FMR1 as a potential candidate gene. Research gaps and potential pitfalls are discussed to inform timely, well-controlled biomarker research that will ultimately promote better diagnosis and treatment of autism and associated conditions. PMID:25420222

TARGETED TREATMENTS IN AUTISM AND FRAGILE X SYNDROME

PubMed Central

Gürkan, C. Kağan; Hagerman, Randi J.

2012-01-01

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 GABAB 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. PMID:23162607

Dynamic Object Representations in Infants with and without Fragile X Syndrome

PubMed Central

Farzin, Faraz; Rivera, Susan M.

2009-01-01

Our visual world is dynamic in nature. The ability to encode, mentally represent, and track an object's identity as it moves across time and space is critical for integrating and maintaining a complete and coherent view of the world. Here we investigated dynamic object processing in typically developing (TD) infants and infants with fragile X syndrome (FXS), a single-gene disorder associated with deficits in dorsal stream functioning. We used the violation of expectation method to assess infants’ visual response to expected versus unexpected outcomes following a brief dynamic (dorsal stream) or static (ventral stream) occlusion event. Consistent with previous reports of deficits in dorsal stream-mediated functioning in individuals with this disorder, these results reveal that, compared to mental age-matched TD infants, infants with FXS could maintain the identity of static, but not dynamic, object information during occlusion. These findings are the first to experimentally evaluate visual object processing skills in infants with FXS, and further support the hypothesis of dorsal stream difficulties in infants with this developmental disorder. PMID:20224809

Fragile X syndrome: panoramic radiographic evaluation of dental anomalies, dental mineralization stage, and mandibular angle.

PubMed

Sabbagh-Haddad, Aida; Haddad, Denise Sabbagh; Michel-Crosato, Edgard; Arita, Emiko Saito

2016-01-01

The purpose of this study was to evaluate the dental radiographic characteristics as described in 40 records of patients with panoramic radiography. The patients were in the range of 6-17 years old, and were divided into two groups (20 subjects who were compatible with the normality standard and 20 individuals diagnosed with the FXS), which were matched for gender and age. Analysis of the panoramic radiographic examination involved the evaluation of dental mineralization stage, mandibular angle size, and presence of dental anomalies in both deciduous and permanent dentitions. The results of radiographic evaluation demonstrated that the chronology of tooth eruption of all third and second lower molars is anticipated in individuals with FXS (p<0.05). In this group, supernumerary deciduous teeth (2.83%), giroversion of permanent teeth (2.31%), and partial anodontia (1.82%) were the most frequent dental anomalies. In addition, an increase was observed in the mandibular angle size in the FXS group (p<0.05). We conclude that knowledge of dental radiographic changes is of great importance for dental surgeons to plan the treatment of these individuals.

Hippocampal dysfunction and cognitive impairment in Fragile-X Syndrome.

PubMed

Bostrom, Crystal; Yau, Suk-Yu; Majaess, Namat; Vetrici, Mariana; Gil-Mohapel, Joana; Christie, Brian R

2016-09-01

Fragile-X Syndrome (FXS) is the most common form of inherited intellectual disability and the leading genetic cause of autism spectrum disorder. FXS is caused by transcriptional silencing of the Fragile X Mental Retardation 1 (Fmr1) gene due to a CGG repeat expansion, resulting in the loss of Fragile X Mental Retardation Protein (FMRP). FMRP is involved in transcriptional regulation and trafficking of mRNA from the nucleus to the cytoplasm and distal sites both in pre- and post-synaptic terminals. Consequently, FXS is a multifaceted disorder associated with impaired synaptic plasticity. One region of the brain that is significantly impacted by the loss of FMRP is the hippocampus, a structure that plays a critical role in the regulation of mood and cognition. This review provides an overview of the neuropathology of Fragile-X Syndrome, highlighting how structural and synaptic deficits in hippocampal subregions, including the CA1 exhibiting exaggerated metabotropic glutamate receptor dependent long-term depression and the dentate gyrus displaying hypofunction of N-methyl-d-aspartate receptors, contribute to cognitive impairments associated with this neurodevelopmental disorder. Copyright © 2016 Elsevier Ltd. All rights reserved.

How common are challenging behaviours amongst individuals with Fragile X Syndrome? A systematic review.

PubMed

Hardiman, Rebecca Lyndsey; McGill, Peter

2018-05-01

Fragile X Syndrome (FXS) appears to be associated with an increased risk for engaging in challenging behaviour, particularly self-injury, relative to those with mixed aetiology learning disabilities. Such behavioural issues are reported to be of high concern for those providing support. As such, this systematic review aimed to gain further epidemiological data regarding challenging behaviours in individuals with FXS, including: self-injurious behaviour (SIB), hand-biting as a specific topography of SIB, aggression and property destruction. Twenty eight manuscripts were identified which reported the prevalence of a relevant topography of behaviour, with widely varying prevalence estimates. Weighted averages of the prevalence of behaviours were calculated across studies. Comparison of proportions revealed significant gender differences and differences in the prevalence of types of behaviour. It is hoped that this comprehensive overview of data on this clinically significant topic will help to inform and drive future investigation to understand and provide effective intervention for the benefit of those with FXS. Crown Copyright © 2018. Published by Elsevier Ltd. All rights reserved.

Characterising repetitive behaviours in young boys with fragile X syndrome

PubMed Central

Oakes, A.; Thurman, A.J.; McDuffie, A.; Bullard, L.M.; Hagerman, R.J.; Abbeduto, L.

2015-01-01

Background Repetitive behaviours are frequently observed in individuals with intellectual disability. The present study examined the profile, inter-correlations, and predictive correlates of repetitive behaviours in males with FXS, the leading inherited cause of intellectual disability. Specific child characteristics examined as predictors included: anxiety, nonverbal cognition, and autism social-affective symptomatology. Method Participants were 39 boys with FXS (aged 6–10 years). Repetitive behaviours were measured using the Repetitive Behavior Scale – Revised (RBS-R) – a 43-item caregiver-report measure normed on individuals with intellectual disability. Results Restricted Interests and Sensory Motor behaviours were reported as most problematic for this sample of boys, whereas Self-injurious behaviours were less problematic. All subscales of the RBS-R were significantly inter-correlated. Nonverbal IQ was negatively related, whereas anxiety and social affective symptoms of ASD were positively related, to scores for Restricted Interests. Anxiety was also positively related to scores for Compulsive behaviours and Ritualistic Sameness behaviours. Conclusions This study provides a preliminary description of repetitive behaviours in males with FXS, which may form the groundwork for future research. PMID:26449367

NMDA receptor hypofunction in the dentate gyrus and impaired context discrimination in adult Fmr1 knockout mice.

PubMed

Eadie, Brennan D; Cushman, Jesse; Kannangara, Timal S; Fanselow, Michael S; Christie, Brian R

2012-02-01

Fragile X syndrome (FXS) is the most common form of inherited intellectual disability in humans. This X-linked disorder is caused by the transcriptional repression of a single gene, Fmr1. The loss of Fmr1 transcription prevents the production of Fragile X mental retardation protein (FMRP) which in turn disrupts the expression of a variety of key synaptic proteins that appear to be important for intellectual ability. A clear link between synaptic dysfunction and behavioral impairment has been elusive, despite the fact that several animal models of FXS have been generated. Here we report that Fmr1 knockout mice exhibit impaired bidirectional synaptic plasticity in the dentate gyrus (DG) of the hippocampus. These deficits are associated with a novel decrease in functional NMDARs (N-methyl-D-aspartate receptors). In addition, mice lacking the Fmr1 gene show impaired performance in a context discrimination task that normally requires functional NMDARs in the DG. These data indicate that Fmr1 deletion results in significant NMDAR-dependent electrophysiological and behavioral impairments specific to the DG. Copyright © 2010 Wiley Periodicals, Inc.

Depression and anxiety symptoms among women who carry the FMR1 premutation: impact of raising a child with fragile X syndrome is moderated by CRHR1 polymorphisms.

PubMed

Hunter, Jessica Ezzell; Leslie, Mary; Novak, Gloria; Hamilton, Debra; Shubeck, Lisa; Charen, Krista; Abramowitz, Ann; Epstein, Michael P; Lori, Adriana; Binder, Elisabeth; Cubells, Joseph F; Sherman, Stephanie L

2012-07-01

The fragile X mental retardation gene, FMR1, contains a polymorphic CGG repeat in the 5'-untranslated region of exon 1. Once unstable, this repeat is capable of expansion across generations. Women who carry a premutation allele (55-199 repeats) are at risk of passing on a full mutation allele (>200 repeats) to their offspring. A full mutation leads to the most common form of inherited intellectual disability, fragile X syndrome (FXS). Mounting evidence suggests that premutation carriers may be vulnerable to symptoms of anxiety and depression. The goal of this study was to test the hypothesis that among women who carry a premutation, the stress of raising a child with FXS would be moderated by genetic factors influencing endogenous cortisol responses, which could in turn modulate anxiety and depression symptoms. To this end, we genotyped single nucleotide polymorphisms (SNPs) at the corticotrophin releasing hormone receptor 1 locus (CRHR1) in 460 women. Participants completed self-report questionnaires assessing symptoms of depression [Centers for Epidemiological Studies Depression Scale (CESD)], anxiety [State-Trait Anxiety Inventory (STAI) and Social Phobia and Anxiety Inventory (SPAI)], and mood [Positive and Negative Affect Schedule (PANAS)]. Results indicate a statistically significant interaction between CRHR1 genotype and the status of raising a child with FXS to predict social anxiety symptoms reported on the SPAI (rs7209436, P = 0.0001). Our data suggest that genetic variants in CRHR1 that associate with differential cortisol activation may also modulate levels of anxiety related to the stress of raising a child with FXS among women who carry an FMR1 premutation. Copyright © 2012 Wiley Periodicals, Inc.

Rescue of Synaptic Phenotypes and Spatial Memory in Young Fragile X Mice.

PubMed

Sun, Miao-Kun; Hongpaisan, Jarin; Alkon, Daniel L

2016-05-01

Fragile X syndrome (FXS) is characterized by synaptic immaturity, cognitive impairment, and behavioral changes. The disorder is caused by transcriptional shutdown in neurons of thefragile X mental retardation 1gene product, fragile X mental retardation protein. Fragile X mental retardation protein is a repressor of dendritic mRNA translation and its silencing leads to dysregulation of synaptically driven protein synthesis and impairments of intellect, cognition, and behavior, and FXS is a disorder that currently has no effective therapeutics. Here, young fragile X mice were treated with chronic bryostatin-1, a relatively selective protein kinase Cεactivator, which induces synaptogenesis and synaptic maturation/repair. Chronic treatment with bryostatin-1 rescues young fragile X mice from the disorder phenotypes, including normalization of most FXS abnormalities in 1) hippocampal brain-derived neurotrophic factor expression, 2) postsynaptic density-95 levels, 3) transformation of immature dendritic spines to mature synapses, 4) densities of the presynaptic and postsynaptic membranes, and 5) spatial learning and memory. The therapeutic effects were achieved without downregulation of metabotropic glutamate receptor (mGluR) 5 in the hippocampus and are more dramatic than those of a late-onset treatment in adult fragile X mice. mGluR5 expression was in fact lower in fragile X mice and its expression was restored with the bryostatin-1 treatment. Our results show that synaptic and cognitive function of young FXS mice can be normalized through pharmacological treatment without downregulation of mGluR5 and that bryostatin-1-like agents may represent a novel class of drugs to treat fragile X mental retardation at a young age and in adults. Copyright © 2016 by The American Society for Pharmacology and Experimental Therapeutics.

High functioning male with fragile X syndrome and fragile X-associated tremor/ataxia syndrome.

PubMed

Basuta, Kirin; Schneider, Andrea; Gane, Louise; Polussa, Jonathan; Woodruff, Bryan; Pretto, Dalyir; Hagerman, Randi; Tassone, Flora

2015-09-01

Fragile X syndrome (FXS) affects individuals with more than 200 CGG repeats (full mutation) in the fragile X mental retardation 1 (FMR1) gene. Those born with FXS experience cognitive and social impairments, developmental delays, and some features of autism spectrum disorders. Carriers of a premutation (55-200 CGG repeats) are generally not severely affected early in life; however, are at high risk of developing the late onset neurodegenerative disorder, Fragile X-associated Tremor/Ataxia Syndrome (FXTAS), or Fragile X-associated Primary Ovarian Insufficiency (FXPOI), and may have other medical conditions such as developmental delay, autism spectrum disorders, hypertension, anxiety, and immune-mediated disorders. Here we present a case of a 58-year-old man with a borderline IQ, average memory skills, and executive function deficits. He met criteria for multiple psychiatric diagnoses and presented with tremor and ataxia, meeting criteria for FXTAS. Molecular testing unveiled a completely unmethylated FMR1 full mutation in peripheral blood mononucleated cells with elevated FMR1 mRNA and premutation alleles of different sizes in two other tissues (primary fibroblasts and sperm), indicating the presence of allele instability based on both inter- and intra-tissue mosaicism. The observation of FXTAS in this case of a full mutation mosaic man suggests that the pathogenic mechanism underlying this disorder is not observed exclusively in premutation carriers as it was originally thought. The concomitant presence of features of FXS and late onset neurological deterioration with probable FXTAS likely result from a combined molecular pathology of elevated FMR1 mRNA levels, a molecular hallmark of FXTAS and low FMRP expression that leads to FXS. © 2015 Wiley Periodicals, Inc.

Fragile X syndrome: panoramic radiographic evaluation of dental anomalies, dental mineralization stage, and mandibular angle

PubMed Central

Sabbagh-Haddad, Aida; Haddad, Denise Sabbagh; Michel-Crosato, Edgard; Arita, Emiko Saito

2016-01-01

ABSTRACT Fragile X syndrome (FXS) is a disorder linked to the chromosome X long arm (Xq27.3), which is identified by a constriction named fragile site. It determines various changes, such as behavioral or emotional problems, learning difficulties, and intellectual disabilities. Craniofacial abnormalities such as elongated and narrow face, prominent forehead, broad nose, large and prominent ear pavilions, strabismus, and myopia are frequent characteristics. Regarding the oral aspects, deep and high-arched palate, mandibular prognathism, and malocclusion are also observed. Objective: The purpose of this study was to evaluate the dental radiographic characteristics as described in 40 records of patients with panoramic radiography. Material and Methods: The patients were in the range of 6–17 years old, and were divided into two groups (20 subjects who were compatible with the normality standard and 20 individuals diagnosed with the FXS), which were matched for gender and age. Analysis of the panoramic radiographic examination involved the evaluation of dental mineralization stage, mandibular angle size, and presence of dental anomalies in both deciduous and permanent dentitions. Results: The results of radiographic evaluation demonstrated that the chronology of tooth eruption of all third and second lower molars is anticipated in individuals with FXS (p<0.05). In this group, supernumerary deciduous teeth (2.83%), giroversion of permanent teeth (2.31%), and partial anodontia (1.82%) were the most frequent dental anomalies. In addition, an increase was observed in the mandibular angle size in the FXS group (p<0.05). Conclusion: We conclude that knowledge of dental radiographic changes is of great importance for dental surgeons to plan the treatment of these individuals. PMID:27812623

Fragile X and autism: Intertwined at the molecular level leading to targeted treatments.

PubMed

Hagerman, Randi; Hoem, Gry; Hagerman, Paul

2010-09-21

Fragile X syndrome (FXS) is caused by an expanded CGG repeat (> 200 repeats) in the 5' untranslated portion of the fragile mental retardation 1 gene (FMR1), leading to deficiency or absence of the FMR1 protein (FMRP). FMRP is an RNA carrier protein that controls the translation of several other genes that regulate synaptic development and plasticity. Autism occurs in approximately 30% of FXS cases, and pervasive developmental disorder, not otherwise specified (PDD-NOS) occurs in an additional 30% of cases. Premutation repeat expansions (55 to 200 CGG repeats) may also give rise to autism spectrum disorders (ASD), including both autism and PDD-NOS, through a different molecular mechanism that involves a direct toxic effect of the expanded CGG repeat FMR1 mRNA. RNA toxicity can also lead to aging effects including tremor, ataxia and cognitive decline, termed fragile X-associated tremor ataxia syndrome (FXTAS), in premutation carriers in late life. In studies of mice bearing premutation expansions, there is evidence of early postnatal neuronal cell toxicity, presenting as reduced cell longevity, decreased dendritic arborization and altered synaptic morphology. There is also evidence of mitochondrial dysfunction in premutation carriers. Many of the problems with cellular dysregulation in both premutation and full mutation neurons also parallel the cellular abnormalities that have been documented in autism without fragile X mutations. Research regarding dysregulation of neurotransmitter systems in FXS, including the metabotropic glutamate receptor (mGluR)1/5 pathway and γ aminobutyric acid (GABA)A pathways, have led to new targeted treatments for FXS. Preliminary evidence suggests that these new targeted treatments will also be beneficial in non-fragile X forms of autism.

Fear-Specific Amygdala Function in Children and Adolescents on the Fragile X Spectrum: A Dosage Response of the FMR1 Gene

PubMed Central

Kim, So-Yeon; Burris, Jessica; Bassal, Frederick; Koldewyn, Kami; Chattarji, Sumantra; Tassone, Flora; Hessl, David; Rivera, Susan M.

2014-01-01

Mutations of the fragile X mental retardation 1 (FMR1) gene are the genetic cause of fragile X syndrome (FXS). The presence of significant socioemotional problems has been well documented in FXS although the brain basis of those deficits remains unspecified. Here, we investigated amygdala dysfunction and its relation to socioemotional deficits and FMR1 gene expression in children and adolescents on the FX spectrum (i.e., individuals whose trinucleotide CGG repeat expansion from 55 to over 200 places them somewhere within the fragile X diagnostic range from premutation to full mutation). Participants performed an fMRI task in which they viewed fearful, happy, and scrambled faces. Neuroimaging results demonstrated that FX participants revealed significantly attenuated amygdala activation in Fearful > Scrambled and Fearful > Happy contrasts compared with their neurotypical counterparts, while showing no differences in amygdala volume. Furthermore, we found significant relationships between FMR1 gene expression, anxiety/social dysfunction scores, and reduced amygdala activation in the FX group. In conclusion, we report novel evidence regarding a dosage response of the FMR1 gene on fear-specific functions of the amygdala, which is associated with socioemotional deficits in FXS. PMID:23146966

Regulation of GABAA receptors by fragile X mental retardation protein

PubMed Central

Liu, Baosong; Li, Lijun; Chen, Juan; Wang, Zefen; Li, Zhiqiang; Wan, Qi

2013-01-01

Fragile X syndrome (FXS) is caused by the loss of fragile X mental retardation protein (FMRP). The deficiency of GABAA receptors (GABAARs) is implicated in FXS. However, the underlying mechanisms remain unclear. To investigate the effect of FMRP on GABAARs, we transfected FMRP cDNAs in rat cortical neurons. We measured the protein expression of GABAARs and phosphatase PTEN, and recorded GABAAR-mediated whole-cell currents in the transfected neurons. We show that the transfection of FMRP cDNAs causes increased protein expression of GABAARs in cortical neurons, but GABAAR-mediated whole-cell currents are not potentiated by FMRP transfection. These results suggest the possibility that intracellular signaling antagonizing GABAAR activity may play a role in inhibiting GABAAR function in FMRP-transfected neurons. We further show that FMRP transfection results in an enhanced protein expression of PTEN, which contributes to the inhibition of GABAAR function in FMRP-transfected neurons. These results indicate that GABAARs are regulated by FMRP through both an up-regulation of GABAAR expression and a PTEN enhancement-induced inhibition of GABAAR function, suggesting that an abnormal regulation of GABAAR and PTEN by the loss of FMRP underlies the pathogenesis of FXS. PMID:24044036

Total body irradiation in a patient with fragile X syndrome for acute lymphoblastic leukemia in preparation for stem cell transplantation: A case report and literature review.

PubMed

Collins, D T; Mannina, E M; Mendonca, M

2015-10-01

Fragile X syndrome (FXS) is a congenital disorder caused by expansion of CGG trinucleotide repeat at the 5' end of the fragile X mental retardation gene 1 (FMR1) on the X chromosome that leads to chromosomal instability and diminished serum levels of fragile X mental retardation protein (FMRP). Afflicted individuals often have elongated features, marfanoid habitus, macroorchidism and intellectual impairment. Evolving literature suggests the condition may actually protect from malignancy while chromosomal instability would presumably elevate the risk. Increased sensitivity to ionizing radiation should also be predicted by unstable sites within the DNA. Interestingly, in this report, we detail a patient with FXS diagnosed with acute lymphoblastic leukemia treated with induction followed by subsequent cycles of hyper-CVAD (cyclophosphamide, vincristine, doxorubicin, dexamethasone) with a complete response who then was recommended to undergo peripheral stem cell transplantation. The patient underwent total body irradiation (TBI) as a component of his conditioning regimen and despite the concern of his clinicians, developed minimal acute toxicity and successful engraftment. The pertinent literature regarding irradiation of patients with FXS is also reviewed. © 2015 Wiley Periodicals, Inc.

Chromosome fragility at FRAXA in human cleavage stage embryos at risk for fragile X syndrome.

PubMed

Verdyck, Pieter; Berckmoes, Veerle; De Vos, Anick; Verpoest, Willem; Liebaers, Inge; Bonduelle, Maryse; De Rycke, Martine

2015-10-01

Fragile X syndrome (FXS), the most common inherited intellectual disability syndrome, is caused by expansion and hypermethylation of the CGG repeat in the 5' UTR of the FMR1 gene. This expanded repeat, also known as the rare fragile site FRAXA, causes X chromosome fragility in cultured cells from patients but only when induced by perturbing pyrimidine synthesis. We performed preimplantation genetic diagnosis (PGD) on 595 blastomeres biopsied from 442 cleavage stage embryos at risk for FXS using short tandem repeat (STR) markers. In six blastomeres, from five embryos an incomplete haplotype was observed with loss of all alleles telomeric to the CGG repeat. In all five embryos, the incomplete haplotype corresponded to the haplotype carrying the CGG repeat expansion. Subsequent analysis of additional blastomeres from three embryos by array comparative genomic hybridization (aCGH) confirmed the presence of a terminal deletion with a breakpoint close to the CGG repeat in two blastomeres from one embryo. A blastomere from another embryo showed the complementary duplication. We conclude that a CGG repeat expansion at FRAXA causes X chromosome fragility in early human IVF embryos at risk for FXS. © 2015 Wiley Periodicals, Inc.

The Fragile X Protein binds mRNAs involved in cancer progression and modulates metastasis formation

PubMed Central

Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; Fata, Giorgio La; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

2013-01-01

The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. PMID:24092663

Early Vocal Development in Autism Spectrum Disorder, Rett Syndrome, and Fragile X Syndrome: Insights from Studies using Retrospective Video Analysis.

PubMed

Roche, Laura; Zhang, Dajie; Bartl-Pokorny, Katrin D; Pokorny, Florian B; Schuller, Björn W; Esposito, Gianluca; Bölte, Sven; Roeyers, Herbert; Poustka, Luise; Gugatschka, Markus; Waddington, Hannah; Vollmann, Ralf; Einspieler, Christa; Marschik, Peter B

2018-03-01

This article provides an overview of studies assessing the early vocalisations of children with autism spectrum disorder (ASD), Rett syndrome (RTT), and fragile X syndrome (FXS) using retrospective video analysis (RVA) during the first two years of life. Electronic databases were systematically searched and a total of 23 studies were selected. These studies were then categorised according to whether children were later diagnosed with ASD (13 studies), RTT (8 studies), or FXS (2 studies), and then described in terms of (a) participant characteristics, (b) control group characteristics, (c) video footage, (d) behaviours analysed, and (e) main findings. This overview supports the use of RVA in analysing the early development of vocalisations in children later diagnosed with ASD, RTT or FXS, and provides an in-depth analysis of vocalisation presentation, complex vocalisation production, and the rate and/or frequency of vocalisation production across the three disorders. Implications are discussed in terms of extending crude vocal analyses to more precise methods that might provide more powerful means by which to discriminate between disorders during early development. A greater understanding of the early manifestation of these disorders may then lead to improvements in earlier detection.

Dendritic mRNA targeting and translation.

PubMed

Kindler, Stefan; Kreienkamp, Hans-Jürgen

2012-01-01

Selective targeting of specific mRNAs into neuronal dendrites and their locally regulated translation at particular cell contact sites contribute to input-specific synaptic plasticity. Thus, individual synapses become decision-making units, which control gene expression in a spatially restricted and nucleus-independent manner. Dendritic targeting of mRNAs is achieved by active, microtubule-dependent transport. For this purpose, mRNAs are packaged into large ribonucleoprotein (RNP) particles containing an array of trans-acting RNA-binding proteins. These are attached to molecular motors, which move their RNP cargo into dendrites. A variety of proteins may be synthesized in dendrites, including signalling and scaffold proteins of the synapse and neurotransmitter receptors. In some cases, such as the alpha subunit of the calcium/calmodulin-dependent protein kinase II (αCaMKII) and the activity-regulated gene of 3.1 kb (Arg3.1, also referred to as activity-regulated cDNA, Arc), their local synthesis at synapses can modulate long-term changes in synaptic efficiency. Local dendritic translation is regulated by several signalling cascades including Akt/mTOR and Erk/MAP kinase pathways, which are triggered by synaptic activity. More recent findings show that miRNAs also play an important role in protein synthesis at synapses. Disruption of local translation control at synapses, as observed in the fragile X syndrome (FXS) and its mouse models and possibly also in autism spectrum disorders, interferes with cognitive abilities in mice and men.

Offering fragile X syndrome carrier screening: a prospective mixed-methods observational study comparing carrier screening of pregnant and non-pregnant women in the general population

PubMed Central

Martyn, M; Anderson, V; Archibald, A; Carter, R; Cohen, J; Delatycki, M; Donath, S; Emery, J; Halliday, J; Hill, M; Sheffield, L; Slater, H; Tassone, F; Younie, S; Metcalfe, S

2013-01-01

Introduction Fragile X syndrome (FXS) is the leading cause of inherited intellectual and developmental disability. Policy development relating to carrier screening programmes for FXS requires input from large studies examining not only test uptake but also psychosocial aspects. This study will compare carrier screening in pregnant and non-pregnant populations, examining informed decision-making, psychosocial issues and health economics. Methods and Analysis Pregnant and non-pregnant women are being recruited from general practices and obstetric services. Women receive study information either in person or through clinic mail outs. Women are provided pretest counselling by a genetic counsellor and make a decision about testing in their own time. Data are being collected from two questionnaires: one completed at the time of making the decision about testing and the second 1 month later. Additional data are gathered through qualitative interviews conducted at several time points with a subset of participating women, including all women with a positive test result, and with staff from recruiting clinics. A minimum sample size of 500 women/group has been calculated to give us 88% power to detect a 10% difference in test uptake and 87% power to detect a 10% difference in informed choice between the pregnant and non-pregnant groups. Questionnaire data will be analysed using descriptive statistics and multivariate logistic regression models. Interview data will be thematically analysed. Willingness-to-pay and cost effectiveness analyses will also be performed. Recruitment started in July 2009 and data collection will be completed by December 2013. Ethics and Dissemination Ethics approval has been granted by the Universities of Melbourne and Western Australia and by recruiting clinics, where required. Results will be reported in peer-reviewed publications, conference presentations and through a website http://www.fragilexscreening.net.au. The results of this study will make a significant contribution to discussions about the wider introduction of population carrier screening for FXS. PMID:24022395

Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures

PubMed Central

Myrick, Leila K.; Deng, Pan-Yue; Hashimoto, Hideharu; Oh, Young Mi; Cho, Yongcheol; Poidevin, Mickael J.; Suhl, Joshua A.; Visootsak, Jeannie; Cavalli, Valeria; Jin, Peng; Cheng, Xiaodong; Warren, Stephen T.; Klyachko, Vitaly A.

2015-01-01

Fragile X syndrome (FXS) results in intellectual disability (ID) most often caused by silencing of the fragile X mental retardation 1 (FMR1) gene. The resulting absence of fragile X mental retardation protein 1 (FMRP) leads to both pre- and postsynaptic defects, yet whether the pre- and postsynaptic functions of FMRP are independent and have distinct roles in FXS neuropathology remain poorly understood. Here, we demonstrate an independent presynaptic function for FMRP through the study of an ID patient with an FMR1 missense mutation. This mutation, c.413G > A (R138Q), preserves FMRP’s canonical functions in RNA binding and translational regulation, which are traditionally associated with postsynaptic compartments. However, neuronally driven expression of the mutant FMRP is unable to rescue structural defects at the neuromuscular junction in fragile x mental retardation 1 (dfmr1)-deficient Drosophila, suggesting a presynaptic-specific impairment. Furthermore, mutant FMRP loses the ability to rescue presynaptic action potential (AP) broadening in Fmr1 KO mice. The R138Q mutation also disrupts FMRP’s interaction with the large-conductance calcium-activated potassium (BK) channels that modulate AP width. These results reveal a presynaptic- and translation-independent function of FMRP that is linked to a specific subset of FXS phenotypes. PMID:25561520

The fragile X protein binds mRNAs involved in cancer progression and modulates metastasis formation.

PubMed

Lucá, Rossella; Averna, Michele; Zalfa, Francesca; Vecchi, Manuela; Bianchi, Fabrizio; La Fata, Giorgio; Del Nonno, Franca; Nardacci, Roberta; Bianchi, Marco; Nuciforo, Paolo; Munck, Sebastian; Parrella, Paola; Moura, Rute; Signori, Emanuela; Alston, Robert; Kuchnio, Anna; Farace, Maria Giulia; Fazio, Vito Michele; Piacentini, Mauro; De Strooper, Bart; Achsel, Tilmann; Neri, Giovanni; Neven, Patrick; Evans, D Gareth; Carmeliet, Peter; Mazzone, Massimiliano; Bagni, Claudia

2013-10-01

The role of the fragile X mental retardation protein (FMRP) is well established in brain, where its absence leads to the fragile X syndrome (FXS). FMRP is almost ubiquitously expressed, suggesting that, in addition to its effects in brain, it may have fundamental roles in other organs. There is evidence that FMRP expression can be linked to cancer. FMR1 mRNA, encoding FMRP, is overexpressed in hepatocellular carcinoma cells. A decreased risk of cancer has been reported in patients with FXS while a patient-case with FXS showed an unusual decrease of tumour brain invasiveness. However, a role for FMRP in regulating cancer biology, if any, remains unknown. We show here that FMRP and FMR1 mRNA levels correlate with prognostic indicators of aggressive breast cancer, lung metastases probability and triple negative breast cancer (TNBC). We establish that FMRP overexpression in murine breast primary tumours enhances lung metastasis while its reduction has the opposite effect regulating cell spreading and invasion. FMRP binds mRNAs involved in epithelial mesenchymal transition (EMT) and invasion including E-cadherin and Vimentin mRNAs, hallmarks of EMT and cancer progression. © 2013 The Authors. Published by John Wiley and Sons, Ltd on behalf of EMBO.

[Triplet expansion cytosine-guanine-guanine: Three cases of OMIM syndrome in the same family].

PubMed

González-Pérez, Jesús; Izquierdo-Álvarez, Silvia; Fuertes-Rodrigo, Cristina; Monge-Galindo, Lorena; Peña-Segura, José Luis; López-Pisón, Francisco Javier

2016-04-01

The dynamic increase in the number of triplet repeats of cytosine-guanine-guanine (CGG) in the FMR1 gene mutation is responsible for three OMIM syndromes with a distinct clinical phenotype: Fragile X syndrome (FXS) and two pathologies in adult carriers of the premutation (55-200 CGG repeats): Primary ovarian insufficiency (FXPOI) and tremor-ataxia syndrome (FXTAS) associated with FXS. CGG mutation dynamics of the FMR1 gene were studied in DNA samples from peripheral blood from the index case and other relatives of first, second and third degree by TP-PCR, and the percentage methylation. Diagnosis of FXS was confirmed in three patients (21.4%), eight patients (57.1%) were confirmed in the premutation range transmitters, one male patient with full mutation/permutation mosaicism (7.1%) and two patients (14.3%) with normal study. Of the eight permutated patients, three had FXPOI and one male patient had FXTAS. Our study suggests the importance of making an early diagnosis of SXF in order to carry out a family study and genetic counselling, which allow the identification of new cases or premutated patients with FMR1 gene- associated syndromes (FXTAS, FXPOI). Copyright © 2015 Elsevier España, S.L.U. All rights reserved.

Detection and Quantification of the Fragile X Mental Retardation Protein 1 (FMRP).

PubMed

LaFauci, Giuseppe; Adayev, Tatyana; Kascsak, Richard; Brown, W Ted

2016-12-09

The final product of FMR1 gene transcription, Fragile X Mental Retardation Protein 1 (FMRP), is an RNA binding protein that acts as a repressor of translation. FMRP is expressed in several tissues and plays important roles in neurogenesis, synaptic plasticity, and ovarian functions and has been implicated in a number of neuropsychological disorders. The loss of FMRP causes Fragile X Syndrome (FXS). In most cases, FXS is due to large expansions of a CGG repeat in FMR1 -normally containing 6-54 repeats-to over 200 CGGs and identified as full mutation (FM). Hypermethylation of the repeat induces FMR1 silencing and lack of FMRP expression in FM male. Mosaic FM males express low levels of FMRP and present a less severe phenotype that inversely correlates with FMRP levels. Carriers of pre-mutations (55-200 CGG) show increased mRNA, and normal to reduced FMRP levels. Alternative splicing of FMR1 mRNA results in 24 FMRP predicted isoforms whose expression are tissues and developmentally regulated. Here, we summarize the approaches used by several laboratories including our own to (a) detect and estimate the amount of FMRP in different tissues, developmental stages and various pathologies; and (b) to accurately quantifying FMRP for a direct diagnosis of FXS in adults and newborns.

Detection and Quantification of the Fragile X Mental Retardation Protein 1 (FMRP)

PubMed Central

LaFauci, Giuseppe; Adayev, Tatyana; Kascsak, Richard; Brown, W. Ted

2016-01-01

The final product of FMR1 gene transcription, Fragile X Mental Retardation Protein 1 (FMRP), is an RNA binding protein that acts as a repressor of translation. FMRP is expressed in several tissues and plays important roles in neurogenesis, synaptic plasticity, and ovarian functions and has been implicated in a number of neuropsychological disorders. The loss of FMRP causes Fragile X Syndrome (FXS). In most cases, FXS is due to large expansions of a CGG repeat in FMR1—normally containing 6–54 repeats—to over 200 CGGs and identified as full mutation (FM). Hypermethylation of the repeat induces FMR1 silencing and lack of FMRP expression in FM male. Mosaic FM males express low levels of FMRP and present a less severe phenotype that inversely correlates with FMRP levels. Carriers of pre-mutations (55–200 CGG) show increased mRNA, and normal to reduced FMRP levels. Alternative splicing of FMR1 mRNA results in 24 FMRP predicted isoforms whose expression are tissues and developmentally regulated. Here, we summarize the approaches used by several laboratories including our own to (a) detect and estimate the amount of FMRP in different tissues, developmental stages and various pathologies; and (b) to accurately quantifying FMRP for a direct diagnosis of FXS in adults and newborns. PMID:27941672

Fragile X protein in newborn dried blood spots.

PubMed

Adayev, Tatyana; LaFauci, Giuseppe; Dobkin, Carl; Caggana, Michele; Wiley, Veronica; Field, Michael; Wotton, Tiffany; Kascsak, Richard; Nolin, Sarah L; Glicksman, Anne; Hosmer, Nicole; Brown, W Ted

2014-10-28

The fragile X syndrome (FXS) results from mutation of the FMR1 gene that prevents expression of its gene product, FMRP. We previously characterized 215 dried blood spots (DBS) representing different FMR1 genotypes and ages with a Luminex-based immunoassay (qFMRP). We found variable FMRP levels in the normal samples and identified affected males by the drastic reduction of FMRP. Here, to establish the variability of expression of FMRP in a larger random population we quantified FMRP in 2,000 anonymous fresh newborn DBS. We also evaluated the effect of long term storage on qFMRP by retrospectively assaying 74 aged newborn DBS that had been stored for 7-84 months that included normal and full mutation individuals. These analyses were performed on 3 mm DBS disks. To identify the alleles associated with the lowest FMRP levels in the fresh DBS, we analyzed the DNA in the samples that were more than two standard deviations below the mean. Analysis of the fresh newborn DBS revealed a broad distribution of FMRP with a mean approximately 7-fold higher than that we previously reported for fresh DBS in normal adults and no samples whose FMRP level indicated FXS. DNA analysis of the lowest FMRP DBS showed that this was the low extreme of the normal range and included a female carrying a 165 CGG repeat premutation. In the retrospective study of aged newborn DBS, the FMRP mean of the normal samples was less than 30% of the mean of the fresh DBS. Despite the degraded signal from these aged DBS, qFMRP identified the FXS individuals. The assay showed that newborn DBS contain high levels of FMRP that will allow identification of males and potentially females, affected by FXS. The assay is also an effective screening tool for aged DBS stored for up to four years.

Parenting of children with Down syndrome compared to fragile X syndrome.

PubMed

Sterling, Audra; Warren, Steven F

2018-01-01

Children with Down syndrome (DS) and fragile X syndrome (FXS) struggle with language development. Parenting variables, such as responsiveness to children's communication attempts (Maternal Responsivity), and techniques used to support and teach appropriate behavior (Behavior Management) are known to have a significant impact on early child development. We examined these two aspects of parenting style via coded, videotaped parent-child interactions in two groups of participants matched on child age (2-5 years) and child expressive language level: mothers of children with DS and mothers of children with FXS. The mothers differed in their use of gestures and redirecting the child's attention. Overall, mothers in both groups of children appeared to adapt appropriately to their children's developmental needs.

The role of the postsynaptic density in the pathology of the fragile X syndrome.

PubMed

Kindler, Stefan; Kreienkamp, Hans-Jürgen

2012-01-01

The protein repertoire of excitatory synapses controls dendritic spine morphology, synaptic plasticity and higher brain functions. In brain neurons, the RNA-associated fragile X mental retardation protein (FMRP) binds in vivo to various transcripts encoding key postsynaptic components and may thereby substantially regulate the molecular composition of dendritic spines. In agreement with this notion functional loss of FMRP in patients affected by the fragile X syndrome (FXS) causes cognitive impairment. Here we address our current understanding of the functional role of individual postsynaptic proteins. We discuss how FMRP controls the abundance of select proteins at postsynaptic sites, which signaling pathways regulate the local activity of FMRP at synapses, and how altered levels of postsynaptic proteins may contribute to FXS pathology.

Activation of 5-HT7 serotonin receptors reverses metabotropic glutamate receptor-mediated synaptic plasticity in wild-type and Fmr1 knockout mice, a model of Fragile X syndrome.

PubMed

Costa, Lara; Spatuzza, Michela; D'Antoni, Simona; Bonaccorso, Carmela M; Trovato, Chiara; Musumeci, Sebastiano A; Leopoldo, Marcello; Lacivita, Enza; Catania, Maria V; Ciranna, Lucia

2012-12-01

Fragile X syndrome (FXS) is a genetic cause of intellectual disability and autism. Fmr1 knockout (Fmr1 KO) mice, an animal model of FXS, exhibit spatial memory impairment and synapse malfunctioning in the hippocampus, with abnormal enhancement of long-term depression mediated by metabotropic glutamate receptors (mGluR-LTD). The neurotransmitter serotonin (5-HT) modulates hippocampal-dependent learning through serotonin 1A (5-HT1A) and serotonin 7 (5-HT7) receptors; the underlying mechanisms are unknown. We used electrophysiology to test the effects of 5-HT on mGluR-LTD in wild-type and Fmr1 KO mice and immunocytochemistry and biotinylation assay to study related changes of 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl)propanoic acid (AMPA) glutamate receptor surface expression. Application of 5-HT or 8-OH-DPAT (a mixed 5-HT1A/5-HT7 agonist) reversed mGluR-LTD in hippocampal slices. Reversal of mGluR-LTD by 8-OH-DPAT persisted in the presence of the 5-HT1A receptor antagonist WAY-100635, was abolished by SB-269970 (5-HT7 receptor antagonist), and was mimicked by LP-211, a novel selective 5-HT7 receptor agonist. Consistently, 8-OH-DPAT decreased mGluR-mediated reduction of AMPA glutamate receptor 2 (GluR2) subunit surface expression in hippocampal slices and cultured hippocampal neurons, an effect mimicked by LP-211 and blocked by SB-269970. In Fmr1 KO mice, mGluR-LTD was abnormally enhanced; similarly to wild-type, 8-OH-DPAT reversed mGluR-LTD and decreased mGluR-induced reduction of surface AMPA receptors, an effect antagonized by SB-269970. Serotonin 7 receptor activation reverses metabotropic glutamate receptor-induced AMPA receptor internalization and LTD both in wild-type and in Fmr1 KO mice, correcting excessive mGluR-LTD. Therefore, selective activation of 5-HT7 receptors may represent a novel strategy in the therapy of FXS. Copyright © 2012 Society of Biological Psychiatry. Published by Elsevier Inc. All rights reserved.

The therapeutic effect of memantine through the stimulation of synapse formation and dendritic spine maturation in autism and fragile X syndrome.

PubMed

Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M; Malik, Mazhar; Brown, W Ted; Li, Xiaohong

2012-01-01

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs.

The Therapeutic effect of Memantine through the Stimulation of Synapse Formation and Dendritic Spine Maturation in Autism and Fragile X Syndrome

PubMed Central

Wei, Hongen; Dobkin, Carl; Sheikh, Ashfaq M.; Malik, Mazhar; Brown, W. Ted; Li, Xiaohong

2012-01-01

Although the pathogenic mechanisms that underlie autism are not well understood, there is evidence showing that metabotropic and ionotropic glutamate receptors are hyper-stimulated and the GABAergic system is hypo-stimulated in autism. Memantine is an uncompetitive antagonist of NMDA receptors and is widely prescribed for treatment of Alzheimer's disease treatment. Recently, it has been shown to improve language function, social behavior, and self-stimulatory behaviors of some autistic subjects. However the mechanism by which memantine exerts its effect remains to be elucidated. In this study, we used cultured cerebellar granule cells (CGCs) from Fmr1 knockout (KO) mice, a mouse model for fragile X syndrome (FXS) and syndromic autism, to examine the effects of memantine on dendritic spine development and synapse formation. Our results show that the maturation of dendritic spines is delayed in Fmr1-KO CGCs. We also detected reduced excitatory synapse formation in Fmr1-KO CGCs. Memantine treatment of Fmr1-KO CGCs promoted cell adhesion properties. Memantine also stimulated the development of mushroom-shaped mature dendritic spines and restored dendritic spine to normal levels in Fmr1-KO CGCs. Furthermore, we demonstrated that memantine treatment promoted synapse formation and restored the excitatory synapses to a normal range in Fmr1-KO CGCs. These findings suggest that memantine may exert its therapeutic capacity through a stimulatory effect on dendritic spine maturation and excitatory synapse formation, as well as promoting adhesion of CGCs. PMID:22615862

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice

PubMed Central

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-01-01

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS. PMID:23148316

Dampened dopamine-mediated neuromodulation in prefrontal cortex of fragile X mice.

PubMed

Paul, Kush; Venkitaramani, Deepa V; Cox, Charles L

2013-02-15

Fragile X syndrome (FXS) is the most common form of inheritable mental retardation caused by transcriptional silencing of the Fmr1 gene resulting in the absence of fragile X mental retardation protein (FMRP). The role of this protein in neurons is complex and its absence gives rise to diverse alterations in neuronal function leading to neurological disorders including mental retardation, hyperactivity, cognitive impairment, obsessive-compulsive behaviour, seizure activity and autism. FMRP regulates mRNA translation at dendritic spines where synapses are formed, and thus the lack of FMRP can lead to disruptions in synaptic transmission and plasticity. Many of these neurological deficits in FXS probably involve the prefrontal cortex, and in this study, we have focused on modulatory actions of dopamine in the medial prefrontal cortex. Our data indicate that dopamine produces a long-lasting enhancement of evoked inhibitory postsynaptic currents (IPSCs) mediated by D1-type receptors seen in wild-type mice; however, such enhancement is absent in the Fmr1 knock-out (Fmr1 KO) mice. The facilitation of IPSCs produced by direct cAMP stimulation was unaffected in Fmr1 KO, but D1 receptor levels were reduced in these animals. Our results show significant disruption of dopaminergic modulation of synaptic transmission in the Fmr1 KO mice and this alteration in inhibitory activity may provide insight into potential targets for the rescue of deficits associated with FXS.

Viewing social scenes: a visual scan-path study comparing fragile X syndrome and Williams syndrome.

PubMed

Williams, Tracey A; Porter, Melanie A; Langdon, Robyn

2013-08-01

Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of socially salient information within scenes to investigate the visual attentional mechanisms of: capture, disengagement, and/or general engagement. Findings revealed that individuals with FXS avoid social information presented centrally, at least initially. The WS findings, on the other hand, provided some evidence that difficulties with attentional disengagement, rather than attentional capture, may play a role in the WS social phenotype. These findings are discussed in relation to the distinct social phenotypes of these two disorders.

National Fragile X Foundation

MedlinePlus

Donate Contact PS3G Home About About Us Finances 2016 Annual Impact Report (PDF) Learn FXS FXPOI FXTAS Newly Diagnosed Premutation Carriers Treatment and Intervention Prevalence,Genetics and Inheritance Testing Webinars Research ...

2-Methyl-6-(phenylethynyl) pyridine (MPEP) reverses maze learning and PSD-95 deficits in Fmr1 knock-out mice.

PubMed

Gandhi, Réno M; Kogan, Cary S; Messier, Claude

2014-01-01

Fragile X Syndrome (FXS) is caused by the lack of expression of the fragile X mental retardation protein (FMRP), which results in intellectual disability and other debilitating symptoms including impairment of visual-spatial functioning. FXS is the only single-gene disorder that is highly co-morbid with autism spectrum disorder and can therefore provide insight into its pathophysiology. Lack of FMRP results in altered group I metabotropic glutamate receptor (mGluR) signaling, which is a target for putative treatments. The Hebb-Williams (H-W) mazes are a set of increasingly complex spatial navigation problems that depend on intact hippocampal and thus mGluR-5 functioning. In the present investigation, we examined whether an antagonist of mGluR-5 would reverse previously described behavioral deficits in fragile X mental retardation 1 knock-out (Fmr1 KO) mice. Mice were trained on a subset of the H-W mazes and then treated with either 20 mg/kg of an mGluR-5 antagonist, 2-Methyl-6-(phenylethynyl) pyridine (MPEP; n = 11) or an equivalent dose of saline (n = 11) prior to running test mazes. Latency and errors were dependent variables recorded during the test phase. Immediately after completing each test, marble-burying behavior was assessed, which confirmed that the drug treatment was pharmacologically active during maze learning. Although latency was not statistically different between the groups, MPEP treated Fmr1 KO mice made significantly fewer errors on mazes deemed more difficult suggesting a reversal of the behavioral deficit. MPEP treated mice were also less perseverative and impulsive when navigating mazes. Furthermore, MPEP treatment reversed post-synaptic density-95 (PSD-95) protein deficits in Fmr1 KO treated mice, whereas levels of a control protein (β-tubulin) remained unchanged. These data further validate MPEP as a potentially beneficial treatment for FXS. Our findings also suggest that adapted H-W mazes may be a useful tool to document alterations in behavioral functioning following pharmacological intervention in FXS.

A Trial of Metformin in Individuals With Fragile X Syndrome

ClinicalTrials.gov

2018-06-05

Fragile X Syndrome; Fragile X Mental Retardation Syndrome; Mental Retardation, X Linked; Genetic Diseases, X-Linked; Trinucleotide Repeat Expansion; Fra(X) Syndrome; Intellectual Disability; FXS; Neurobehavioral Manifestations; Sex Chromosome Disorders

Fragile X-Associated Primary Ovarian Insufficiency (FXPOI)

MedlinePlus

Donate Contact PS3G Home About About Us Finances 2016 Annual Impact Report Learn Fragile X Syndrome FXS Resources by Age Group Clinical Practice Consensus Documents FXPOI FXTAS Newly Diagnosed Premutation Carriers ...

What It Means to be a Carrier

MedlinePlus

Donate Contact PS3G Home About About Us Finances 2016 Annual Impact Report Learn Fragile X Syndrome FXS Resources by Age Group Clinical Practice Consensus Documents FXPOI FXTAS Newly Diagnosed Premutation Carriers ...

Investigating the Receptive-Expressive Vocabulary Profile in Children with Idiopathic ASD and Comorbid ASD and Fragile X Syndrome.

PubMed

Haebig, Eileen; Sterling, Audra

2017-02-01

Previous work has noted that some children with autism spectrum disorder (ASD) display weaknesses in receptive vocabulary relative to expressive vocabulary abilities. The current study extended previous work by examining the receptive-expressive vocabulary profile in boys with idiopathic ASD and boys with concomitant ASD and fragile X syndrome (ASD + FXS). On average, boys with ASD + FXS did not display the same atypical receptive-expressive profile as boys with idiopathic ASD. Notably, there was variation in vocabulary abilities and profiles in both groups. Although we did not identify predictors of receptive-expressive differences, we demonstrated that nonverbal IQ and expressive vocabulary positively predicted concurrent receptive vocabulary knowledge and receptive vocabulary predicted expressive vocabulary. We discuss areas of overlap and divergence in subgroups of ASD.

Investigating the Receptive-Expressive Vocabulary Profile in Children with Idiopathic ASD and Comorbid ASD and Fragile X Syndrome

PubMed Central

Sterling, Audra

2016-01-01

Previous work has noted that some children with autism spectrum disorder (ASD) display weaknesses in receptive vocabulary relative to expressive vocabulary abilities. The current study extended previous work by examining the receptive-expressive vocabulary profile in boys with idiopathic ASD and boys with concomitant ASD and fragile X syndrome (ASD + FXS). On average, boys with ASD + FXS did not display the same atypical receptive-expressive profile as boys with idiopathic ASD. Notably, there was variation in vocabulary abilities and profiles in both groups. Although we did not identify predictors of receptive-expressive differences, we demonstrated that nonverbal IQ and expressive vocabulary positively predicted concurrent receptive vocabulary knowledge and receptive vocabulary predicted expressive vocabulary. We discuss areas of overlap and divergence in subgroups of ASD. PMID:27796729

Imbalance between Glutamate and GABA in Fmr1 Knockout Astrocytes Influences Neuronal Development

PubMed Central

Wang, Lu; Wang, Yan; Zhou, Shimeng; Yang, Liukun; Shi, Qixin; Li, Yujiao; Zhang, Kun; Yang, Le; Zhao, Minggao; Yang, Qi

2016-01-01

Fragile X syndrome (FXS) is a form of inherited mental retardation that results from the absence of the fragile X mental retardation protein (FMRP), the product of the Fmr1 gene. Numerous studies have shown that FMRP expression in astrocytes is important in the development of FXS. Although astrocytes affect neuronal dendrite development in Fmr1 knockout (KO) mice, the factors released by astrocytes are still unclear. We cultured wild type (WT) cortical neurons in astrocyte-conditioned medium (ACM) from WT or Fmr1 KO mice. Immunocytochemistry and Western blotting were performed to detect the dendritic growth of both WT and KO neurons. We determined glutamate and γ-aminobutyric acid (GABA) levels using high-performance liquid chromatography (HPLC). The total neuronal dendritic length was reduced when cultured in the Fmr1 KO ACM. This neurotoxicity was triggered by an imbalanced release of glutamate and GABA from Fmr1 KO astrocytes. We found increased glutaminase and GABA transaminase (GABA-T) expression and decreased monoamine oxidase B expression in Fmr1 KO astrocytes. The elevated levels of glutamate contributed to oxidative stress in the cultured neurons. Vigabatrin (VGB), a GABA-T inhibitor, reversed the changes caused by glutamate and GABA release in Fmr1 KO astrocytes and the abnormal behaviors in Fmr1 KO mice. Our results indicate that the imbalance in the astrocytic glutamate and GABA release may be involved in the neuropathology and the underlying symptoms of FXS, and provides a therapeutic target for treatment. PMID:27517961

Public Health Literature Review of Fragile X Syndrome

PubMed Central

Raspa, Melissa; Wheeler, Anne C.; Riley, Catharine

2017-01-01

OBJECTIVES The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families. METHODS An electronic literature search was conducted, guided by a variety of key words. The search focused on 4 areas of both clinical and public health importance: (1) the full mutation phenotype, (2) developmental trajectories across the life span, (3) available interventions and treatments, and (4) impact on the family. A total of 661 articles were examined and 203 were included in the review. RESULTS The information is presented in the following categories: developmental profile (cognition, language, functional skills, and transition to adulthood), social-emotional profile (cooccurring psychiatric conditions and behavior problems), medical profile (physical features, seizures, sleep, health problems, and physiologic features), treatment and interventions (educational/behavioral, allied health services, and pharmacologic), and impact on the family (family environment and financial impact). Research gaps also are presented. CONCLUSIONS The identification and treatment of FXS remains an important public health and clinical concern. The information presented in this article provides a more robust understanding of FXS and the impact of this complex condition for pediatricians. Despite a wealth of information about the condition, much work remains to fully support affected individuals and their families. PMID:28814537

Public Health Literature Review of Fragile X Syndrome.

PubMed

Raspa, Melissa; Wheeler, Anne C; Riley, Catharine

2017-06-01

The purpose of this systematic literature review is to describe what is known about fragile X syndrome (FXS) and to identify research gaps. The results can be used to help inform future public health research and provide pediatricians with up-to-date information about the implications of the condition for individuals and their families. An electronic literature search was conducted, guided by a variety of key words. The search focused on 4 areas of both clinical and public health importance: (1) the full mutation phenotype, (2) developmental trajectories across the life span, (3) available interventions and treatments, and (4) impact on the family. A total of 661 articles were examined and 203 were included in the review. The information is presented in the following categories: developmental profile (cognition, language, functional skills, and transition to adulthood), social-emotional profile (cooccurring psychiatric conditions and behavior problems), medical profile (physical features, seizures, sleep, health problems, and physiologic features), treatment and interventions (educational/behavioral, allied health services, and pharmacologic), and impact on the family (family environment and financial impact). Research gaps also are presented. The identification and treatment of FXS remains an important public health and clinical concern. The information presented in this article provides a more robust understanding of FXS and the impact of this complex condition for pediatricians. Despite a wealth of information about the condition, much work remains to fully support affected individuals and their families. Copyright © 2017 by the American Academy of Pediatrics.

Exaggerated Cap-Dependent Translation as a Mechanism for Corticostriatal Dysfunction in Fragile X Syndrome Model Mice

DTIC Science & Technology

2016-10-01

AWARD NUMBER: W81XWH-15-1-0361 TITLE: Exaggerated Cap- Dependent Translation as a Mechanism for Corticostriatal Dysfunction in Fragile X Syndrome...DATES  COVERED 09/30/2015-09/29/2016 4. TITLE  AND  SUBTITLE 5a.  CONTRACT  NUMBER   Exaggerated Cap- Dependent Translation as a Mechanism for...cap-­ dependent  translation  inhibitors.  Our  specific  tasks   are  centered  on  a  proteomic  study  of  FXS  striatal  synapses  by  using  a

Daily Health Symptoms of Mothers of Adolescents and Adults with Fragile X Syndrome and Mothers of Adolescents and Adults with Autism Spectrum Disorder

PubMed Central

Seltzer, Marsha Mailick; Greenberg, Jan S.

2012-01-01

Health symptoms of mothers of adolescents and adults with fragile X syndrome (FXS; n = 112) were compared to a nationally-representative sample of mothers of similarly-aged children without disabilities (n = 230) as well as to a sample of mothers of adolescents and adults with autism spectrum disorders (ASD; n = 96). Health symptoms experienced in the previous 24 h were recorded during 8 consecutive days of a daily diary study. Both mothers of a son or daughter with FXS and mothers of a son or daughter with ASD had a higher proportion of days with headaches, backaches, muscle soreness, fatigue, and hot flashes than mothers of children without disabilities. Mothers of children with disabilities appear to be at particular risk for health problems, highlighting a need for comprehensive services for families across the lifespan. PMID:22167342

Maternal responses to child frustration and requests for help in dyads with fragile X syndrome.

PubMed

Wheeler, A C; Hatton, D; Holloway, V T; Sideris, J; Neebe, E C; Roberts, J E; Reznick, J S

2010-06-01

Variability in behaviour displayed by children with fragile X syndrome (FXS) may be partially attributable to environmental factors such as maternal responsivity. The purpose of this study was to explore variables associated with maternal behaviour during a task designed to elicit frustration in their children with FXS. Forty-six mother-child dyads, in which the child had full-mutation FXS, were observed in their homes during a task designed to elicit frustration in the child. Each child was given a wrong set of keys and asked to open a box to retrieve a desired toy. Mothers were provided with the correct set of keys and instructed to intervene when they perceived their child was getting too frustrated. Child-expressed frustration and requests for help and maternal behaviours (comforting, negative control, and encouraging/directing) were observed and coded. Maternal variables (e.g. depression, stress, education levels), child variables (e.g. autistic behaviours, age, medication use) and child behaviours (frustration, requests for help) were explored as predictors of maternal behaviour. Almost all mothers intervened to help their children and most used encouraging/directing behaviours, whereas very few used comforting or negative control. Child age and child behaviours during the frustrating event were significant predictors of encouraging/directing behaviours in the mothers. Children whose mothers reported higher depressive symptomology used fewer requests for help, and mothers of children with more autistic behaviours used more negative control. The results of this study suggest that child age and immediate behaviours are more strongly related to maternal responsivity than maternal traits such as depression and stress.

EMQN best practice guidelines for the molecular genetic testing and reporting of fragile X syndrome and other fragile X-associated disorders

PubMed Central

Biancalana, Valérie; Glaeser, Dieter; McQuaid, Shirley; Steinbach, Peter

2015-01-01

Different mutations occurring in the unstable CGG repeat in 5' untranslated region of FMR1 gene are responsible for three fragile X-associated disorders. An expansion of over ∼200 CGG repeats when associated with abnormal methylation and inactivation of the promoter is the mutation termed ‘full mutation' and is responsible for fragile X syndrome (FXS), a neurodevelopmental disorder described as the most common cause of inherited intellectual impairment. The term ‘abnormal methylation' is used here to distinguish the DNA methylation induced by the expanded repeat from the ‘normal methylation' occurring on the inactive X chromosomes in females with normal, premutation, and full mutation alleles. All male and roughly half of the female full mutation carriers have FXS. Another anomaly termed ‘premutation' is characterized by the presence of 55 to ∼200 CGGs without abnormal methylation, and is the cause of two other diseases with incomplete penetrance. One is fragile X-associated primary ovarian insufficiency (FXPOI), which is characterized by a large spectrum of ovarian dysfunction phenotypes and possible early menopause as the end stage. The other is fragile X-associated tremor/ataxia syndrome (FXTAS), which is a late onset neurodegenerative disorder affecting males and females. Because of the particular pattern and transmission of the CGG repeat, appropriate molecular testing and reporting is very important for the optimal genetic counselling in the three fragile X-associated disorders. Here, we describe best practice guidelines for genetic analysis and reporting in FXS, FXPOI, and FXTAS, including carrier and prenatal testing. PMID:25227148

A combination of ascorbic acid and α-tocopherol to test the effectiveness and safety in the fragile X syndrome: study protocol for a phase II, randomized, placebo-controlled trial.

PubMed

de Diego-Otero, Yolanda; Calvo-Medina, Rocio; Quintero-Navarro, Carolina; Sánchez-Salido, Lourdes; García-Guirado, Francisco; del Arco-Herrera, Ignacio; Fernández-Carvajal, Isabel; Ferrando-Lucas, Teresa; Caballero-Andaluz, Rafaela; Pérez-Costillas, Lucia

2014-09-03

Fragile X syndrome (FXS) is an inherited neurodevelopmental condition characterised by behavioural, learning disabilities, physical and neurological symptoms. In addition, an important degree of comorbidity with autism is also present. Considered a rare disorder affecting both genders, it first becomes apparent during childhood with displays of language delay and behavioural symptoms.Main aim: To show whether the combination of 10 mg/kg/day of ascorbic acid (vitamin C) and 10 mg/kg/day of α-tocopherol (vitamin E) reduces FXS symptoms among male patients ages 6 to 18 years compared to placebo treatment, as measured on the standardized rating scales at baseline, and after 12 and 24 weeks of treatment.Secondary aims: To assess the safety of the treatment. To describe behavioural and cognitive changes revealed by the Developmental Behaviour Checklist Short Form (DBC-P24) and the Wechsler Intelligence Scale for Children-Revised. To describe metabolic changes revealed by blood analysis. To measure treatment impact at home and in an academic environment. A phase II randomized, double-blind pilot clinical trial. male children and adolescents diagnosed with FXS, in accordance with a standardized molecular biology test, who met all the inclusion criteria and none of the exclusion criteria. clinical data, blood analysis, Wechsler Intelligence Scale for Children-Revised, Conners parent and teacher rating scale scores and the DBC-P24 results will be obtained at the baseline (t0). Follow up examinations will take place at 12 weeks (t1) and 24 weeks (t2) of treatment. A limited number of clinical trials have been carried out on children with FXS, but more are necessary as current treatment possibilities are insufficient and often provoke side effects. In the present study, we sought to overcome possible methodological problems by conducting a phase II pilot study in order to calculate the relevant statistical parameters and determine the safety of the proposed treatment. The results will provide evidence to improve hyperactivity control and reduce behavioural and learning problems using ascorbic acid (vitamin C) and α-tocopherol (vitamin E). The study protocol was approved by the Regional Government Committee for Clinical Trials in Andalusia and the Spanish agency for drugs and health products. ClinicalTrials.gov Identifier: NCT01329770 (29 March 2011).

Learning and memory deficits consequent to reduction of the fragile X mental retardation protein result from metabotropic glutamate receptor-mediated inhibition of cAMP signaling in Drosophila.

PubMed

Kanellopoulos, Alexandros K; Semelidou, Ourania; Kotini, Andriana G; Anezaki, Maria; Skoulakis, Efthimios M C

2012-09-19

Loss of the RNA-binding fragile X protein [fragile X mental retardation protein (FMRP)] results in a spectrum of cognitive deficits, the fragile X syndrome (FXS), while aging individuals with decreased protein levels present with a subset of these symptoms and tremor. The broad range of behavioral deficits likely reflects the ubiquitous distribution and multiple functions of the protein. FMRP loss is expected to affect multiple neuronal proteins and intracellular signaling pathways, whose identity and interactions are essential in understanding and ameliorating FXS symptoms. We used heterozygous mutants and targeted RNA interference-mediated abrogation in Drosophila to uncover molecular pathways affected by FMRP reduction. We present evidence that FMRP loss results in excess metabotropic glutamate receptor (mGluR) activity, attributable at least in part to elevation of the protein in affected neurons. Using high-resolution behavioral, genetic, and biochemical analyses, we present evidence that excess mGluR upon FMRP attenuation is linked to the cAMP decrement reported in patients and models, and underlies olfactory associative learning and memory deficits. Furthermore, our data indicate positive transcriptional regulation of the fly fmr1 gene by cAMP, via protein kinase A, likely through the transcription factor CREB. Because the human Fmr1 gene also contains CREB binding sites, the interaction of mGluR excess and cAMP signaling defects we present suggests novel combinatorial pharmaceutical approaches to symptom amelioration upon FMRP attenuation.

Fragile X syndrome in females - a familial case report and review of the literature.

PubMed

Stembalska, Agnieszka; Łaczmańska, Izabela; Gil, Justyna; Pesz, Karolina A

2016-01-01

Fragile X syndrome (FXS), one of the manifestations of FMR1-related disorders, is one of the most frequent genetic causes of intellectual disability. In over 99% of all cases it results from the expansion of CGG repeats in the 5'-untranslated region of the FMR1 gene and presents in males and in about 50% of the females with an FMR1 full mutation, usually with a milder phenotype. Although the morphologic and behavioral phenotype in males is a well-recognized entity, the presentation in females is variable and not as specific. The objective of this paper is to present a family with quite a severe expression of the disorder in two sisters with a full mutation. We report on a two-generation family where both males and females were found to be affected by FXS. We also present the diagnostic pathway and methods that led to the diagnosis of fragile X syndrome in the two sisters, as well as the method that explained the normal phenotype in their mother. The CGG repeats analysis in the FMR1 gene showed one normal allele and one allele with a full mutation in both sisters (probands) and their mother. A full mutation was also found in three male cousins of the probands. The analysis of the X-chromosome methylation status has shown a random X inactivation in proband 1 and 2 and a non-random one in the proband's mother, with the normal allele predominantly active. The reasons for different clinical presentations are discussed; moreover a review of the literature on females with FXS is presented. We hope that this paper will facilitate the future diagnosis of fragile X syndromes in females.

Programming social behavior by the maternal fragile X protein.

PubMed

Zupan, B; Sharma, A; Frazier, A; Klein, S; Toth, M

2016-07-01

The developing fetus and neonate are highly sensitive to maternal environment. Besides the well-documented effects of maternal stress, nutrition and infections, maternal mutations, by altering the fetal, perinatal and/or early postnatal environment, can impact the behavior of genetically normal offspring. Mutation/premutation in the X-linked FMR1 (encoding the translational regulator FMRP) in females, although primarily responsible for causing fragile X syndrome (FXS) in their children, may also elicit such maternal effects. We showed that a deficit in maternal FMRP in mice results in hyperactivity in the genetically normal offspring. To test if maternal FMRP has a broader intergenerational effect, we measured social behavior, a core dimension of neurodevelopmental disorders, in offspring of FMRP-deficient dams. We found that male offspring of Fmr1(+/-) mothers, independent of their own Fmr1 genotype, exhibit increased approach and reduced avoidance toward conspecific strangers, reminiscent of 'indiscriminate friendliness' or the lack of stranger anxiety, diagnosed in neglected children and in patients with Asperger's and Williams syndrome. Furthermore, social interaction failed to activate mesolimbic/amygdala regions, encoding social aversion, in these mice, providing a neurobiological basis for the behavioral abnormality. This work identifies a novel role for FMRP that extends its function beyond the well-established genetic function into intergenerational non-genetic inheritance/programming of social behavior and the corresponding neuronal circuit. As FXS premutation and some psychiatric conditions that can be associated with reduced FMRP expression are more prevalent in mothers than full FMR1 mutation, our findings potentially broaden the significance of FMRP-dependent programming of social behavior beyond the FXS population. © 2016 John Wiley & Sons Ltd and International Behavioural and Neural Genetics Society.

White matter microstructural abnormalities in girls with chromosome 22q11.2 deletion syndrome, Fragile X or Turner syndrome as evidenced by diffusion tensor imaging

PubMed Central

Villalon, Julio; Jahanshad, Neda; Beaton, Elliott; Toga, Arthur W.; Thompson, Paul M.; Simon, Tony J.

2014-01-01

Children with chromosome 22q11.2 Deletion Syndrome (22q11.2DS), Fragile X Syndrome (FXS), or Turner Syndrome (TS) are considered to belong to distinct genetic groups, as each disorder is caused by separate genetic alterations. Even so, they have similar cognitive and behavioral dysfunctions, particularly in visuospatial and numerical abilities. To assess evidence for common underlying neural microstructural alterations, we set out to determine whether these groups have partially overlapping white matter abnormalities, relative to typically developing controls. We scanned 101 female children between 7 and 14 years old: 25 with 22q11.2DS, 18 with FXS, 17 with TS, and 41 aged-matched controls using diffusion tensor imaging (DTI). Anisotropy and diffusivity measures were calculated and all brain scans were nonlinearly aligned to population and site-specific templates. We performed voxel-based statistical comparisons of the DTI-derived metrics between each disease group and the controls, while adjusting for age. Girls with 22q11.2DS showed lower fractional anisotropy (FA) than controls in the association fibers of the superior and inferior longitudinal fasciculi, the splenium of the corpus callosum, and the corticospinal tract. FA was abnormally lower in girls with FXS in the posterior limbs of the internal capsule, posterior thalami, and precentral gyrus. Girls with TS had lower FA in the inferior longitudinal fasciculus, right internal capsule and left cerebellar peduncle. Partially overlapping neurodevelopmental anomalies were detected in all three neurogenetic disorders. Altered white matter integrity in the superior and inferior longitudinal fasciculi and thalamic to frontal tracts may contribute to the behavioral characteristics of all of these disorders. PMID:23602925

Therapy service use among individuals with fragile X syndrome: findings from a US parent survey.

PubMed

Martin, G E; Ausderau, K K; Raspa, M; Bishop, E; Mallya, U; Bailey, D B

2013-09-01

Fragile X syndrome (FXS) is known to be associated with a range of developmental challenges, yet the occurrence and intensity of therapy services along with associated factors have not been determined. In a US national survey, caregivers provided information regarding the therapy services received by their sons (n = 1013) and daughters (n = 283) with FXS (from birth to 63 years; mean = 15.6 years, SD = 10.6). Caregivers reported (1) type, (2) amount, (3) location, and (4) overall satisfaction with services. Associations with other child variables and family income were also examined. Key findings included that 72% of males and 47% of females were currently receiving at least one type of therapy service; the most common services for both males and females were speech-language therapy (ST) and occupational therapy (OT). Overall, males were more likely to receive therapy services as well as a greater number of services than females. Autism status was significantly associated with both males and females receiving ST and males receiving OT and behaviour management therapy. Therapies were provided in a variety of locations, and parents were generally satisfied with the amount and quality of therapy services. Age-related declines were evident in the use of services for both males and females, with very few individuals receiving any therapy services after 20 years of age. This study provides a baseline description of the current state of therapy services for children with FXS, laying a foundation for future research and recommendations for service provision and policy. © 2012 The Authors. Journal of Intellectual Disability Research © 2012 John Wiley & Sons Ltd, MENCAP & IASSID.

Negotiating Desires and Options: How Mothers Who Carry the Fragile X Gene Experience Reproductive Decisions

PubMed Central

Raspberry, Kelly Amanda; Skinner, Debra

2011-01-01

This paper contributes an empirically-based analysis of how women negotiate reproductive desires and constructions of risk in light of genetic information for a single gene disorder with known inheritance patterns. Fragile X syndrome (FXS) is the most common cause of inherited intellectual disability and female carriers have a 50% probability with each pregnancy of transmitting the FX gene. We present data from interviews conducted with 108 mothers across the U.S. who participated in a longitudinal, mixed methods study on family adaptations to FXS and who have at least one child with FXS. Women’s accounts of their reproductive desires, actions, and reasoning indicate that the known 50% risk of transmitting the FX gene was a powerful deterrent to attempting to have more children through unmediated pregnancy. The majority (77%) decided not to have any more biological children after carrier diagnosis. This decision often required revising previous plans for how many children they would have, how and when they would have them, and what kind of mothers they would be. However, genetic risk was not a primary consideration in the reproductive calculations of 22 women who chose to continue planned and unplanned unmediated pregnancies. Though women’s reproductive negotiations are constrained by medical discourse and practices, they are also unpredictable and emerge out of lived experiences and sometimes ambivalent ways of reckoning. While increased availability and accuracy of genetic information and testing contribute to certain forms of family planning that prioritize genetic risk management, we also find that some families call upon alternative understandings and desires for making a family to articulate genetic risk and negotiate their reproductive futures. PMID:21333433

Concurrent Relations between Face Scanning and Language: A Cross-Syndrome Infant Study

PubMed Central

D’Souza, Dean; D’Souza, Hana; Johnson, Mark H.; Karmiloff-Smith, Annette

2015-01-01

Typically developing (TD) infants enhance their learning of spoken language by observing speakers’ mouth movements. Given the fact that word learning is seriously delayed in most children with neurodevelopmental disorders, we hypothesized that this delay partly results from differences in visual face scanning, e.g., focusing attention away from the mouth. To test this hypothesis, we used an eye tracker to measure visual attention in 95 infants and toddlers with Down syndrome (DS), fragile X syndrome (FXS), and Williams syndrome (WS), and compared their data to 25 chronological- and mental-age matched 16-month-old TD controls. We presented participants with two talking faces (one on each side of the screen) and a sound (/ga/). One face (the congruent face) mouthed the syllable that the participants could hear (i.e., /ga/), while the other face (the incongruent face) mouthed a different syllable (/ba/) from the one they could hear. As expected, we found that TD children with a relatively large vocabulary made more fixations to the mouth region of the incongruent face than elsewhere. However, toddlers with FXS or WS who had a relatively large receptive vocabulary made more fixations to the eyes (rather than the mouth) of the incongruent face. In DS, by contrast, fixations to the speaker’s overall face (rather than to her eyes or mouth) predicted vocabulary size. These findings suggest that, at some point in development, different processes or strategies relating to visual attention are involved in language acquisition in DS, FXS, and WS. This knowledge may help further explain why language is delayed in children with neurodevelopmental disorders. It also raises the possibility that syndrome-specific interventions should include an early focus on efficient face-scanning behaviour. PMID:26426329

Concurrent Relations between Face Scanning and Language: A Cross-Syndrome Infant Study.

PubMed

D'Souza, Dean; D'Souza, Hana; Johnson, Mark H; Karmiloff-Smith, Annette

2015-01-01

Typically developing (TD) infants enhance their learning of spoken language by observing speakers' mouth movements. Given the fact that word learning is seriously delayed in most children with neurodevelopmental disorders, we hypothesized that this delay partly results from differences in visual face scanning, e.g., focusing attention away from the mouth. To test this hypothesis, we used an eye tracker to measure visual attention in 95 infants and toddlers with Down syndrome (DS), fragile X syndrome (FXS), and Williams syndrome (WS), and compared their data to 25 chronological- and mental-age matched 16-month-old TD controls. We presented participants with two talking faces (one on each side of the screen) and a sound (/ga/). One face (the congruent face) mouthed the syllable that the participants could hear (i.e., /ga/), while the other face (the incongruent face) mouthed a different syllable (/ba/) from the one they could hear. As expected, we found that TD children with a relatively large vocabulary made more fixations to the mouth region of the incongruent face than elsewhere. However, toddlers with FXS or WS who had a relatively large receptive vocabulary made more fixations to the eyes (rather than the mouth) of the incongruent face. In DS, by contrast, fixations to the speaker's overall face (rather than to her eyes or mouth) predicted vocabulary size. These findings suggest that, at some point in development, different processes or strategies relating to visual attention are involved in language acquisition in DS, FXS, and WS. This knowledge may help further explain why language is delayed in children with neurodevelopmental disorders. It also raises the possibility that syndrome-specific interventions should include an early focus on efficient face-scanning behaviour.

Fragile X Syndrome--From Genes to Cognition

ERIC Educational Resources Information Center

Schneider, A.; Hagerman, R. J.; Hessl, D.

2009-01-01

Fragile X syndrome (FXS), a single gene disorder with an expanded CGG allele on the X chromosome, is the most common form of inherited cognitive impairment. The cognitive deficit ranges from mild learning disabilities to severe intellectual disability. The phenotype includes hyperactivity, short attention span, emotional problems including…

Social Cognition in Adolescent Girls with Fragile X Syndrome

ERIC Educational Resources Information Center

Turkstra, Lyn S.; Abbeduto, Leonard; Meulenbroek, Peter

2014-01-01

This study aimed to characterize social cognition, executive functions (EFs), and everyday social functioning in adolescent girls with fragile X syndrome, and identify relationships among these variables. Participants were 20 girls with FXS and 20 age-matched typically developing peers. Results showed significant between-groups differences in…

Newborn Screening for Fragile X Syndrome

ERIC Educational Resources Information Center

Bailey, Donald B., Jr.

2004-01-01

Newborn screening for fragile X syndrome (FXS) is technically possible, and in the relatively near future accurate and inexpensive screening technologies are likely to be available. When that happens, will America's public health system adopt newborn screening for fragile X syndrome? This article addresses this issue by first placing screening for…

The Neuroanatomy and Neuroendocrinology of Fragile X Syndrome

ERIC Educational Resources Information Center

Hessl, David; Rivera, Susan M.; Reiss, Allan L.

2004-01-01

Fragile X syndrome (FXS), caused by a single gene mutation on the X chromosome, offers a unique opportunity for investigation of gene-brain-behavior relationships. Recent advances in molecular genetics, human brain imaging, and behavioral studies have started to unravel the complex pathways leading to the cognitive, psychiatric, and physical…

Attentional Set-Shifting in Fragile X Syndrome

ERIC Educational Resources Information Center

Van der Molen, M. J. W.; Van der Molen, M. W.; Ridderinkhof, K. R.; Hamel, B. C. J.; Curfs, L. M. G.; Ramakers, G. J. A.

2012-01-01

The ability to flexibly adapt to the changing demands of the environment is often reported as a core deficit in fragile X syndrome (FXS). However, the cognitive processes that determine this attentional set-shifting deficit remain elusive. The present study investigated attentional set-shifting ability in fragile X syndrome males with the…

Finiteness Marking in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Sterling, Audra M.; Rice, Mabel L.; Warren, Steven F.

2012-01-01

Purpose: The current study investigated finiteness marking (e.g., he walk "s", he walk "ed") in boys with fragile X syndrome (FXS); the boys were grouped based on receptive vocabulary (i.e., borderline, impaired). Method: Twenty-one boys with the full mutation of fragile X, between the ages of 8 and 16 years participated. The…

Cognitive, Environmental, and Linguistic Predictors of Syntax in Fragile X Syndrome and Down Syndrome

ERIC Educational Resources Information Center

Estigarribia, Bruno; Martin, Gary E.; Roberts, Joanne E.

2012-01-01

Purpose: To examine which cognitive, environmental, and speech-language variables predict expressive syntax in boys with fragile X syndrome (FXS), boys with Down syndrome (DS), and typically developing (TD) boys, and whether predictive relationships differed by group. Method: We obtained Index of Productive Syntax ( Scarborough, 1990) scores for…

78 FR 31948 - Government-Owned Inventions; Availability for Licensing

Federal Register 2010, 2011, 2012, 2013, 2014

2013-05-28

... listed below are owned by an agency of the U.S. Government and are available for licensing in the U.S. in... coverage for companies and may also be available for licensing. FOR FURTHER INFORMATION CONTACT: Licensing... precise and reliable quantification. Currently, there is no approved drug to treat FXS. The invention...

Language Skills of Males with Fragile X Syndrome or Nonsyndromic Autism Spectrum Disorder

ERIC Educational Resources Information Center

Thurman, Angela John; McDuffie, Andrea; Hagerman, Randi J.; Josol, Cynde K.; Abbeduto, Leonard

2017-01-01

Despite the similarities observed between the fragile X syndrome (FXS) and autism spectrum disorder (ASD) phenotypes, few studies have compared their behavioral profiles outside of ASD symptomatology. In the present study, we sought to compare lexical and grammatical abilities in these two conditions. Comparisons of language abilities in both of…

Viewing Social Scenes: A Visual Scan-Path Study Comparing Fragile X Syndrome and Williams Syndrome

ERIC Educational Resources Information Center

Williams, Tracey A.; Porter, Melanie A.; Langdon, Robyn

2013-01-01

Fragile X syndrome (FXS) and Williams syndrome (WS) are both genetic disorders which present with similar cognitive-behavioral problems, but distinct social phenotypes. Despite these social differences both syndromes display poor social relations which may result from abnormal social processing. This study aimed to manipulate the location of…

The Emergence of Effortful Control in Young Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Robinson, Marissa; Klusek, Jessica; Poe, Michele D.; Hatton, Deborah D.; Roberts, Jane E.

2018-01-01

Effortful control, or the ability to suppress a dominant response to perform a subdominant response, is an early-emerging temperament trait that is linked with positive social-emotional development. Fragile X syndrome (FXS) is a single-gene disorder characterized by hallmark regulatory impairments, suggesting diminished effortful control. This…

Fragile X Syndrome. Early Developments. Volume 8, Number 2, Summer 2004

ERIC Educational Resources Information Center

Manuel, John

2004-01-01

Eleven years ago, FPG Child Development Institute (FPG) launched a longitudinal study of a little known form of mental retardation known as fragile X syndrome (FXS). The Carolina Fragile X Project has since grown into a multidisciplinary team studying diverse aspects of the condition, ranging from early identification to school performance. The…

Diverse Profiles of Anxiety Related Disorders in Fragile X, Cornelia de Lange and Rubinstein-Taybi Syndromes

ERIC Educational Resources Information Center

Crawford, Hayley; Waite, Jane; Oliver, Chris

2017-01-01

Anxiety disorders are heightened in specific genetic syndromes in comparison to intellectual disability of heterogeneous aetiology. In this study, we described and contrasted anxiety symptomatology in fragile X (FXS), Cornelia de Lange (CdLS) and Rubinstein-Taybi syndromes (RTS), and compared the symptomatology to normative data for…

Emotion Recognition and Visual-Scan Paths in Fragile X Syndrome

ERIC Educational Resources Information Center

Shaw, Tracey A.; Porter, Melanie A.

2013-01-01

This study investigated emotion recognition abilities and visual scanning of emotional faces in 16 Fragile X syndrome (FXS) individuals compared to 16 chronological-age and 16 mental-age matched controls. The relationships between emotion recognition, visual scan-paths and symptoms of social anxiety, schizotypy and autism were also explored.…

Correlates across the Structural, Functional, and Molecular Phenotypes of Fragile X Syndrome

ERIC Educational Resources Information Center

Beckel-Mitchener, Andrea; Greenough, William T.

2004-01-01

Fragile X syndrome (FXS) is characterized by a pattern of morphological, functional, and molecular characteristics with, in at least some cases, apparent relationships among phenotypic features at different levels. Gross morphology differences in the sizes of some human brain regions are accompanied by fine structural alterations in the shapes and…

Attendance at Fragile X Specialty Clinics: Facilitators and Barriers

ERIC Educational Resources Information Center

Kidd, Sharon A.; Raspa, Melissa; Clark, Renée; Usrey-Roos, Holly; Wheeler, Anne C.; Liu, Jessica A.; Wylie, Amanda; Sherman, Stephanie L.

2017-01-01

The objectives were to describe the demographic characteristics of children with Fragile X syndrome (FXS) and to determine predictors of attendance at Fragile X (FX) clinics. Findings from the Community Support Network (CSN) and Our Fragile X World (OFXW) samples showed that children who attended FX Clinics were mostly male, high-school aged or…

Behavioral Markers of Emergent Stranger Anxiety in Infants and Toddlers with Fragile X Syndrome

ERIC Educational Resources Information Center

Tonnsen, Bridgette; Scherr, Jessica; Reisinger, Debra; Roberts, Jane

2017-01-01

Studying anxiety in neurogenetic syndromes may inform the intersection of biological and developmental risks, facilitating effective and targeted interventions. We longitudinally examined stranger fear in infants and toddlers with fragile X syndrome (FXS; n = 46) and typical controls (n = 33), as well as associations between observed stranger fear…

A Multidisciplinary Approach to the Management of Individuals with Fragile X Syndrome

ERIC Educational Resources Information Center

Alanay, Y.; Unal, F.; Turanli, G.; Alikasifoglu, M.; Alehan, D.; Akyol, U.; Belgin, E.; Sener, C.; Aktas, D.; Boduroglu, I.; Utine, E.; Volkan-Salanci, B.; Ozusta, S.; Genc, A.; Basar, F.; Sevinc, S.; Tuncbilek, E.

2007-01-01

Background: Fragile X syndrome (FXS) is the most common inherited form of intellectual disability. Since the identification of the responsible gene ("FMR1") and its protein (FMRP), there has been enormous progress in both clinical and pathogenetic research on the neurobehavioural aspects of the condition. However, studies regarding other medical…

Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density

NASA Astrophysics Data System (ADS)

Ferron, Laurent; Nieto-Rostro, Manuela; Cassidy, John S.; Dolphin, Annette C.

2014-04-01

Fragile X syndrome (FXS), the most common heritable form of mental retardation, is characterized by synaptic dysfunction. Synaptic transmission depends critically on presynaptic calcium entry via voltage-gated calcium (CaV) channels. Here we show that the functional expression of neuronal N-type CaV channels (CaV2.2) is regulated by fragile X mental retardation protein (FMRP). We find that FMRP knockdown in dorsal root ganglion neurons increases CaV channel density in somata and in presynaptic terminals. We then show that FMRP controls CaV2.2 surface expression by targeting the channels to the proteasome for degradation. The interaction between FMRP and CaV2.2 occurs between the carboxy-terminal domain of FMRP and domains of CaV2.2 known to interact with the neurotransmitter release machinery. Finally, we show that FMRP controls synaptic exocytosis via CaV2.2 channels. Our data indicate that FMRP is a potent regulator of presynaptic activity, and its loss is likely to contribute to synaptic dysfunction in FXS.

Where Environment Meets Cognition: A Focus on Two Developmental Intellectual Disability Disorders

PubMed Central

Ossowski, S.

2016-01-01

One of the most challenging questions in neuroscience is to dissect how learning and memory, the foundational pillars of cognition, are grounded in stable, yet plastic, gene expression states. All known epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodelling, and noncoding RNAs regulate brain gene expression, both during neurodevelopment and in the adult brain in processes related to cognition. On the other hand, alterations in the various components of the epigenetic machinery have been linked to well-known causes of intellectual disability disorders (IDDs). Two examples are Down Syndrome (DS) and Fragile X Syndrome (FXS), where global and local epigenetic alterations lead to impairments in synaptic plasticity, memory, and learning. Since epigenetic modifications are reversible, it is theoretically possible to use epigenetic drugs as cognitive enhancers for the treatment of IDDs. Epigenetic treatments act in a context specific manner, targeting different regions based on cell and state specific chromatin accessibility, facilitating the establishment of the lost balance. Here, we discuss epigenetic studies of IDDs, focusing on DS and FXS, and the use of epidrugs in combinatorial therapies for IDDs. PMID:27547454

Where Environment Meets Cognition: A Focus on Two Developmental Intellectual Disability Disorders.

PubMed

Toma, I De; Gil, L Manubens; Ossowski, S; Dierssen, M

2016-01-01

One of the most challenging questions in neuroscience is to dissect how learning and memory, the foundational pillars of cognition, are grounded in stable, yet plastic, gene expression states. All known epigenetic mechanisms such as DNA methylation and hydroxymethylation, histone modifications, chromatin remodelling, and noncoding RNAs regulate brain gene expression, both during neurodevelopment and in the adult brain in processes related to cognition. On the other hand, alterations in the various components of the epigenetic machinery have been linked to well-known causes of intellectual disability disorders (IDDs). Two examples are Down Syndrome (DS) and Fragile X Syndrome (FXS), where global and local epigenetic alterations lead to impairments in synaptic plasticity, memory, and learning. Since epigenetic modifications are reversible, it is theoretically possible to use epigenetic drugs as cognitive enhancers for the treatment of IDDs. Epigenetic treatments act in a context specific manner, targeting different regions based on cell and state specific chromatin accessibility, facilitating the establishment of the lost balance. Here, we discuss epigenetic studies of IDDs, focusing on DS and FXS, and the use of epidrugs in combinatorial therapies for IDDs.

The Fragile X Mental Retardation 1 Gene (FMR1): Historical Perspective, Phenotypes, Mechanism, Pathology, and Epidemiology

PubMed Central

Grigsby, Jim

2016-01-01

Objectives To provide an historical perspective and overview of the phenotypes, mechanism, pathology, and epidemiology of the fragile X-associated tremor/ataxia syndrome (FXTAS) for neuropsychologists. Methods Selective review of the literature on FXTAS. Results FXTAS is an X-linked neurodegenerative disorder of late onset. One of several phenotypes associated with different mutations of the fragile X mental retardation 1 gene (FMR1), FXTAS involves progressive action tremor, gait ataxia, and impaired executive functioning, among other features. It affects carriers of the FMR1 premutation, which may expand when passed from a mother to her children, in which case it is likely to cause fragile X syndrome (FXS), the most common inherited developmental disability. Conclusion This review briefly summarizes current knowledge of the mechanisms, epidemiology, and mode of transmission of FXTAS and FXS, as well as the neuropsychological, neurologic, neuropsychiatric, neuropathologic, and neuroradiologic phenotypes of FXTAS. Because it was only recently identified, FXTAS is not well known to most practitioners, and it remains largely misdiagnosed, despite the fact that its prevalence may be relatively high. PMID:27356167

The fragile X mental retardation 1 gene (FMR1): historical perspective, phenotypes, mechanism, pathology, and epidemiology.

PubMed

Grigsby, Jim

2016-08-01

To provide an historical perspective and overview of the phenotypes, mechanism, pathology, and epidemiology of the fragile X-associated tremor/ataxia syndrome (FXTAS) for neuropsychologists. Selective review of the literature on FXTAS. FXTAS is an X-linked neurodegenerative disorder of late onset. One of several phenotypes associated with different mutations of the fragile X mental retardation 1 gene (FMR1), FXTAS involves progressive action tremor, gait ataxia, and impaired executive functioning, among other features. It affects carriers of the FMR1 premutation, which may expand when passed from a mother to her children, in which case it is likely to cause fragile X syndrome (FXS), the most common inherited developmental disability. This review briefly summarizes current knowledge of the mechanisms, epidemiology, and mode of transmission of FXTAS and FXS, as well as the neuropsychological, neurologic, neuropsychiatric, neuropathologic, and neuroradiologic phenotypes of FXTAS. Because it was only recently identified, FXTAS is not well known to most practitioners, and it remains largely misdiagnosed, despite the fact that its prevalence may be relatively high.

Impaired bidirectional NMDA receptor dependent synaptic plasticity in the dentate gyrus of adult female Fmr1 heterozygous knockout mice.

PubMed

Yau, S Y; Bostrom, C A; Chiu, J; Fontaine, C J; Sawchuk, S; Meconi, A; Wortman, R C; Truesdell, E; Truesdell, A; Chiu, C; Hryciw, B N; Eadie, B D; Ghilan, M; Christie, B R

2016-12-01

Fragile-X syndrome (FXS) is caused by the transcriptional repression of the Fmr1 gene resulting in loss of the Fragile-X mental retardation protein (FMRP). This leads to cognitive impairment in both male and female patients, however few studies have focused on the impact of FXS in females. Significant cognitive impairment has been reported in approximately 35% of women who exhibit a heterozygous Fmr1 gene mutation, however to date there is a paucity of information regarding the mechanistic underpinnings of these deficits. We, and others, have recently reported that there is significant impairment in N-methyl-d-aspartate receptor (NMDAR)-dependent long-term potentiation (LTP) and long-term depression (LTD) in the hippocampal dentate gyrus (DG) of male Fmr1 knock out mice. Here we examined if female mice displaying a heterozygous loss of the Fmr1 gene (Fmr1 +/- ) would exhibit similar impairments in DG-dependent spatial memory processing and NMDAR hypofunction. We found that Female Fmr1 +/- mice did not show impaired metabotropic glutamate receptor (mGluR)-LTD in the CA1 region, and could perform well on a temporal ordering task that is thought to involve this brain region. In contrast, female Fmr1 +/- mice showed impairments in a pattern separation task thought to involve the DG, and also displayed a significant impairment in both NMDAR-dependent LTD and LTP in this region. The LTP impairment could be rescued by administering the NMDAR co-agonist, glycine. Our data suggests that NMDAR hypofunction in the DG may partly contribute to learning and memory impairment in female Fmr1 +/- mice. Targeting NMDAR-dependent mechanisms may offer hope as a new therapeutic approach for treating female FXS patients with learning and memory impairments. Copyright © 2016 Elsevier Inc. All rights reserved.

In vivo neuronal function of the fragile X mental retardation protein is regulated by phosphorylation

PubMed Central

Coffee, R. Lane; Williamson, Ashley J.; Adkins, Christopher M.; Gray, Marisa C.; Page, Terry L.; Broadie, Kendal

2012-01-01

Fragile X syndrome (FXS), caused by loss of the Fragile X Mental Retardation 1 (FMR1) gene product (FMRP), is the most common heritable cause of intellectual disability and autism spectrum disorders. It has been long hypothesized that the phosphorylation of serine 500 (S500) in human FMRP controls its function as an RNA-binding translational repressor. To test this hypothesis in vivo, we employed neuronally targeted expression of three human FMR1 transgenes, including wild-type (hFMR1), dephosphomimetic (S500A-hFMR1) and phosphomimetic (S500D-hFMR1), in the Drosophila FXS disease model to investigate phosphorylation requirements. At the molecular level, dfmr1 null mutants exhibit elevated brain protein levels due to loss of translational repressor activity. This defect is rescued for an individual target protein and across the population of brain proteins by the phosphomimetic, whereas the dephosphomimetic phenocopies the null condition. At the cellular level, dfmr1 null synapse architecture exhibits increased area, branching and bouton number. The phosphomimetic fully rescues these synaptogenesis defects, whereas the dephosphomimetic provides no rescue. The presence of Futsch-positive (microtubule-associated protein 1B) supernumerary microtubule loops is elevated in dfmr1 null synapses. The human phosphomimetic restores normal Futsch loops, whereas the dephosphomimetic provides no activity. At the behavioral level, dfmr1 null mutants exhibit strongly impaired olfactory associative learning. The human phosphomimetic targeted only to the brain-learning center restores normal learning ability, whereas the dephosphomimetic provides absolutely no rescue. We conclude that human FMRP S500 phosphorylation is necessary for its in vivo function as a neuronal translational repressor and regulator of synaptic architecture, and for the manifestation of FMRP-dependent learning behavior. PMID:22080836

Excitability is increased in hippocampal CA1 pyramidal cells of Fmr1 knockout mice

PubMed Central

Luque, M. Angeles; Beltran-Matas, Pablo; Marin, M. Carmen; Torres, Blas

2017-01-01

Fragile X syndrome (FXS) is caused by a failure of neuronal cells to express the gene encoding the fragile mental retardation protein (FMRP). Clinical features of the syndrome include intellectual disability, learning impairment, hyperactivity, seizures and anxiety. Fmr1 knockout (KO) mice do not express FMRP and, as a result, reproduce some FXS behavioral abnormalities. While intrinsic and synaptic properties of excitatory cells in various part of the brain have been studied in Fmr1 KO mice, a thorough analysis of action potential characteristics and input-output function of CA1 pyramidal cells in this model is lacking. With a view to determining the effects of the absence of FMRP on cell excitability, we studied rheobase, action potential duration, firing frequency–current intensity relationship and action potential after-hyperpolarization (AHP) in CA1 pyramidal cells of the hippocampus of wild type (WT) and Fmr1 KO male mice. Brain slices were prepared from 8- to 12-week-old mice and the electrophysiological properties of cells recorded. Cells from both groups had similar resting membrane potentials. In the absence of FMRP expression, cells had a significantly higher input resistance, while voltage threshold and depolarization voltage were similar in WT and Fmr1 KO cell groups. No changes were observed in rheobase. The action potential duration was longer in the Fmr1 KO cell group, and the action potential firing frequency evoked by current steps of the same intensity was higher. Moreover, the gain (slope) of the relationship between firing frequency and injected current was 1.25-fold higher in the Fmr1 KO cell group. Finally, AHP amplitude was significantly reduced in the Fmr1 KO cell group. According to these data, FMRP absence increases excitability in hippocampal CA1 pyramidal cells. PMID:28931075

Neuron class-specific requirements for Fragile X Mental Retardation Protein in critical period development of calcium signaling in learning and memory circuitry.

PubMed

Doll, Caleb A; Broadie, Kendal

2016-05-01

Neural circuit optimization occurs through sensory activity-dependent mechanisms that refine synaptic connectivity and information processing during early-use developmental critical periods. Fragile X Mental Retardation Protein (FMRP), the gene product lost in Fragile X syndrome (FXS), acts as an activity sensor during critical period development, both as an RNA-binding translation regulator and channel-binding excitability regulator. Here, we employ a Drosophila FXS disease model to assay calcium signaling dynamics with a targeted transgenic GCaMP reporter during critical period development of the mushroom body (MB) learning/memory circuit. We find FMRP regulates depolarization-induced calcium signaling in a neuron-specific manner within this circuit, suppressing activity-dependent calcium transients in excitatory cholinergic MB input projection neurons and enhancing calcium signals in inhibitory GABAergic MB output neurons. Both changes are restricted to the developmental critical period and rectified at maturity. Importantly, conditional genetic (dfmr1) rescue of null mutants during the critical period corrects calcium signaling defects in both neuron classes, indicating a temporally restricted FMRP requirement. Likewise, conditional dfmr1 knockdown (RNAi) during the critical period replicates constitutive null mutant defects in both neuron classes, confirming cell-autonomous requirements for FMRP in developmental regulation of calcium signaling dynamics. Optogenetic stimulation during the critical period enhances depolarization-induced calcium signaling in both neuron classes, but this developmental change is eliminated in dfmr1 null mutants, indicating the activity-dependent regulation requires FMRP. These results show FMRP shapes neuron class-specific calcium signaling in excitatory vs. inhibitory neurons in developing learning/memory circuitry, and that FMRP mediates activity-dependent regulation of calcium signaling specifically during the early-use critical period. Copyright © 2016 Elsevier Inc. All rights reserved.

Infant Development in Fragile X Syndrome: Cross-Syndrome Comparisons

ERIC Educational Resources Information Center

Roberts, Jane E.; McCary, Lindsay M.; Shinkareva, Svetlana V.; Bailey, Donald B., Jr.

2016-01-01

This study examined the developmental profile of male infants with fragile X syndrome (FXS) and its divergence from typical development and development of infants at high risk for autism associated with familial recurrence (ASIBs). Participants included 174 boys ranging in age from 5 to 28 months. Cross-sectional profiles on the Mullen Scales of…

Reliability of Eye Tracking and Pupillometry Measures in Individuals with Fragile X Syndrome

ERIC Educational Resources Information Center

Farzin, Faraz; Scaggs, Felicia; Hervey, Crystal; Berry-Kravis, Elizabeth; Hessl, David

2011-01-01

Recent insight into the underlying molecular and cellular mechanisms of fragile X syndrome (FXS) has led to the proposal and development of new pharmaceutical treatment strategies, and the initiation of clinical trials aimed at correcting core symptoms of the developmental disorder. Consequently, there is an urgent and critical need for outcome…

Autism Symptomatology in Boys with Fragile X Syndrome: A Cross Sectional Developmental Trajectories Comparison with Nonsyndromic Autism Spectrum Disorder

ERIC Educational Resources Information Center

Thurman, Angela John; McDuffie, Andrea; Kover, Sara T.; Hagerman, Randi J.; Abbeduto, Leonard

2015-01-01

Although males with fragile X syndrome (FXS) are frequently described as demonstrating autism symptomatology, there is much debate regarding whether the behavioral symptoms representing the core domains of autism are the result of the same or different underlying neurological/psychological mechanisms. The present study used a cross-sectional…

Discriminating Down Syndrome and Fragile X Syndrome Based on Language Ability

ERIC Educational Resources Information Center

Finestack, Lizbeth H.; Sterling, Audra M.; Abbeduto, Leonard

2013-01-01

This study compared the receptive and expressive language profiles of verbally expressive children and adolescents with Down Syndrome (DS) and those with Fragile X syndrome (FXS) and examined the extent to which these profiles reliably differentiate the diagnostic groups. A total of twenty-four verbal participants with DS (mean age: 12 years),…

Differential Relationships of Anxiety and Autism Symptoms on Social Skills in Young Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Reisinger, Debra L.; Roberts, Jane E.

2017-01-01

Social skills are critical for academic, social, and psychological success of children with both typical and atypical development. Boys with fragile X syndrome (FXS) are at high risk for social skill impairments, given intellectual impairments and secondary conditions. The present study examines the impact of adaptive behavior, autism symptoms,…

Change in the Behavioral Phenotype of Adolescents and Adults with FXS: Role of the Family Environment

ERIC Educational Resources Information Center

Smith, Leann E.; Hong, Jinkuk; Greenberg, Jan S.; Mailick, Marsha R.

2016-01-01

The present study examined trajectories of adaptive behavior, behavior problems, psychological symptoms, and autism symptoms in adolescents and adults with fragile X syndrome (n = 147) over a three-year period. Adaptive behavior significantly increased over time, particularly for adolescents, and the severity of behavior problems decreased over…

A Screening Tool to Measure Eye Contact Avoidance in Boys with Fragile X Syndrome

ERIC Educational Resources Information Center

Hall, Scott S.; Venema, Kaitlin M.

2017-01-01

We examined the reliability, validity and factor structure of the Eye Contact Avoidance Scale (ECAS), a new 15-item screening tool designed to measure eye contact avoidance in individuals with fragile X syndrome (FXS). Internal consistency of the scale was acceptable to excellent and convergent validity with the Social Responsiveness Scale, Second…

A Comparative Study of Educational Provision for Children with Neurogenetic Syndromes: Parent and Teacher Survey

ERIC Educational Resources Information Center

Reilly, C.; Senior, J.; Murtagh, L.

2015-01-01

Background: A number of neurogenetic syndromes have a high association with special educational needs including fragile X syndrome (FXS), Prader-Willi syndrome (PWS), Williams syndrome (WS) and Velo-Cardio-Facial syndrome (VCFS). There is a paucity of research on educational provision for children affected by these syndromes. Method: Parents…

Correlates of Maternal Behaviours in Mothers of Children with Fragile X Syndrome

ERIC Educational Resources Information Center

Wheeler, Anne; Hatton, Deborah; Reichardt, Alison; Bailey, Don

2007-01-01

Background: The behaviours of 24 mothers of children with fragile X syndrome (FXS) with their affected children were examined during planned observations in their homes. The goal of this study was to describe concurrent maternal interactive behaviour and the factors that influence the type and frequency of these behaviours within this group.…

Fragile X Mental Retardation Protein Regulates Heterosynaptic Plasticity in the Hippocampus

ERIC Educational Resources Information Center

Connor, Steven A.; Hoeffer, Charles A.; Klann, Eric; Nguyen, Peter V.

2011-01-01

Silencing of a single gene, FMR1, is linked to a highly prevalent form of mental retardation, characterized by social and cognitive impairments, known as fragile X syndrome (FXS). The FMR1 gene encodes fragile X mental retardation protein (FMRP), which negatively regulates translation. Knockout of Fmr1 in mice results in enhanced long-term…

An Indirect Examination of the Function of Problem Behavior Associated with Fragile X Syndrome and Smith-Magenis Syndrome

ERIC Educational Resources Information Center

Langthorne, Paul; McGill, Peter

2012-01-01

Fragile X syndrome (FXS) and Smith-Magenis syndrome (SMS) are associated with a number of specific topographies of problem behavior. Very few studies have examined the function served by problem behavior in these groups. Using the Questions About Behavioral Function scale Matson and Vollmer (User's guide: questions about behavioral function…

Identification of Expanded Alleles of the "FMR1" Gene in the CHildhood Autism Risks from Genes and Environment (CHARGE) Study

ERIC Educational Resources Information Center

Tassone, Flora; Choudhary, Nimrah S.; Tassone, Federica; Durbin-Johnson, Blythe; Hansen, Robin; Hertz-Picciotto, Irva; Pessah, Isaac

2013-01-01

Fragile X syndrome (FXS) is a neuro-developmental disorder characterized by intellectual disabilities and autism spectrum disorders (ASD). Expansion of a CGG trinucleotide repeat (greater than 200 repeats) in the 5'UTR of the fragile X mental retardation gene, is the single most prevalent cause of cognitive disabilities. Several screening studies…

Examining the Language Phenotype in Children with Typical Development, Specific Language Impairment, and Fragile X Syndrome

ERIC Educational Resources Information Center

Haebig, Eileen; Sterling, Audra; Hoover, Jill

2016-01-01

Purpose: One aspect of morphosyntax, finiteness marking, was compared in children with fragile X syndrome (FXS), specific language impairment (SLI), and typical development matched on mean length of utterance (MLU). Method: Nineteen children with typical development (mean age = 3.3 years), 20 children with SLI (mean age = 4.9 years), and 17 boys…

Differential Impact of the "FMR1" Gene on Visual Processing in Fragile X Syndrome

ERIC Educational Resources Information Center

Kogan, Cary S.; Boutet, Isabelle; Cornish, Kim; Zangenehpour, Shahin; Mullen, Kathy T.; Holden, Jeanette J. A.; Kaloustian, Vazken M. Der; Andermann, Eva; Chaudhuri, Avi

2004-01-01

Fragile X syndrome (FXS) is the most common form of heritable mental retardation, affecting (~ around) 1 in 4000 males. The syndrome arises from expansion of a trinucleotide repeat in the 5'-untranslated region of the fragile X mental retardation 1 ("FMR1") gene, leading to methylation of the promoter sequence and lack of the fragile X mental…

Delineation of Behavioral Phenotypes in Genetic Syndromes: Characteristics of Autism Spectrum Disorder, Affect and Hyperactivity

ERIC Educational Resources Information Center

Oliver, Chris; Berg, Katy; Moss, Jo; Arron, Kate; Burbidge, Cheryl

2011-01-01

We investigated autism spectrum disorder (ASD) symptomatology, hyperactivity and affect in seven genetic syndromes; Angelman (AS; n = 104), Cri du Chat (CdCS; 58), Cornelia de Lange (CdLS; 101), Fragile X (FXS; 191), Prader-Willi (PWS; 189), Smith-Magenis (SMS; 42) and Lowe (LS; 56) syndromes (age range 4-51). ASD symptomatology was heightened in…

Autism Spectrum Phenotype in Males and Females with Fragile X Full Mutation and Premutation

ERIC Educational Resources Information Center

Clifford, Sally; Dissanayake, Cheryl; Bui, Quang M.; Huggins, Richard; Taylor, Annette K.; Loesch, Danuta Z.

2007-01-01

The behavioural phenotype of autism was assessed in individuals with full mutation and premutation fragile X syndrome (FXS) using the Autism Diagnostic Observation Scale-Generic (ADOS-G) and the Autism Diagnostic Interview (ADI-R). The participants, aged 5-80 years, comprised 33 males and 31 females with full mutation, 7 males and 43 females with…

Use of Emotional Cues for Lexical Learning: A Comparison of Autism Spectrum Disorder and Fragile X Syndrome

ERIC Educational Resources Information Center

Thurman, Angela John; McDuffie, Andrea; Kover, Sara T.; Hagerman, Randi; Channell, Marie Moore; Mastergeorge, Ann; Abbeduto, Leonard

2015-01-01

The present study evaluated the ability of males with fragile X syndrome (FXS), nonsyndromic autism spectrum disorder (ASD), or typical development to learn new words by using as a cue to the intended referent an emotional reaction indicating a successful (excitement) or unsuccessful (disappointment) search for a novel object. Performance for all…

Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia.

PubMed

Hwang, Yun Tae; Dudding, Tracy; Aliaga, Solange Mabel; Arpone, Marta; Francis, David; Li, Xin; Slater, Howard Robert; Rogers, Carolyn; Bretherton, Lesley; du Sart, Desirée; Heard, Robert; Godler, David Eugeny

2016-09-21

Mosaicism for FMR1 premutation (PM: 55-199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)-a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen.

Role of maternal gesture use in speech use by children with fragile X syndrome.

PubMed

Hahn, Laura J; Zimmer, B Jean; Brady, Nancy C; Swinburne Romine, Rebecca E; Fleming, Kandace K

2014-05-01

The purpose of this study was to investigate how maternal gesture relates to speech production by children with fragile X syndrome (FXS). Participants were 27 young children with FXS (23 boys, 4 girls) and their mothers. Videotaped home observations were conducted between the ages of 25 and 37 months (toddler period) and again between the ages of 60 and 71 months (child period). The videos were later coded for types of maternal utterances and maternal gestures that preceded child speech productions. Children were also assessed with the Mullen Scales of Early Learning at both ages. Maternal gesture use in the toddler period was positively related to expressive language scores at both age periods and was related to receptive language scores in the child period. Maternal proximal pointing, in comparison to other gestures, evoked more speech responses from children during the mother-child interactions, particularly when combined with wh-questions. This study adds to the growing body of research on the importance of contextual variables, such as maternal gestures, in child language development. Parental gesture use may be an easily added ingredient to parent-focused early language intervention programs.

The Fragile X Protein and Genome Function.

PubMed

Dockendorff, Thomas C; Labrador, Mariano

2018-05-23

The fragile X syndrome (FXS) arises from loss of expression or function of the FMR1 gene and is one of the most common monogenic forms of intellectual disability and autism. During the past two decades of FXS research, the fragile X mental retardation protein (FMRP) has been primarily characterized as a cytoplasmic RNA binding protein that facilitates transport of select RNA substrates through neural projections and regulation of translation within synaptic compartments, with the protein products of such mRNAs then modulating cognitive functions. However, the presence of a small fraction of FMRP in the nucleus has long been recognized. Accordingly, recent studies have uncovered several mechanisms or pathways by which FMRP influences nuclear gene expression and genome function. Some of these pathways appear to be independent of the classical role for FMRP as a regulator of translation and point to novel functions, including the possibility that FMRP directly participates in the DNA damage response and in the maintenance of genome stability. In this review, we highlight these advances and discuss how these new findings could contribute to our understanding of FMRP in brain development and function, the neural pathology of fragile X syndrome, and perhaps impact of future therapeutic considerations.

Enacting genetic responsibility: experiences of mothers who carry the fragile X gene

PubMed Central

Raspberry, Kelly; Skinner, Debra

2010-01-01

A woman who carries the gene for fragile X syndrome (FXS) has a 50 per cent chance per pregnancy of passing the gene to her sons and daughters. In this paper we analyse interview data from mothers who are carriers of the FX gene, and who have at least one child with FXS, to examine how their understandings and enactments of reproductive options, obligations, and responsibilities support an expanded notion of genetic responsibility. Accounts of 108 women from across the United States show that the majority of mothers chose not to have another biological child once they learned their carrier status. They discussed genetic responsibility and reproductive agency in terms of an obligation not to risk having another child who carried the gene, although their accounts reflected the tensions that arose from managing oneself as a genetically at-risk actor. Another 22 mothers either purposefully became pregnant or continued an unplanned pregnancy after finding out their carrier status. These mothers' accounts reflect an expanded version of genetic responsibility that incorporates ideas and values beyond managing risk in what it means to act responsibly in light of genetic knowledge. PMID:21054442

Effect of Speaker Gaze on Word Learning in Fragile X Syndrome: A Comparison with Nonsyndromic Autism Spectrum Disorder

ERIC Educational Resources Information Center

Benjamin, David P.; McDuffie, Andrea S.; Thurman, Angela J.; Kover, Sara T.; Mastergeorge, Ann M.; Hagerman, Randi J.; Abbeduto, Leonard

2015-01-01

Purpose: This study examined use of a speaker's direction of gaze during word learning by boys with fragile X syndrome (FXS), boys with nonsyndromic autism spectrum disorder (ASD), and typically developing (TD) boys. Method: A fast-mapping task with follow-in and discrepant labeling conditions was administered. We expected that the use of speaker…

Global Identification of Disease-Associated Genes in Fragile X Cells

DTIC Science & Technology

2017-03-01

identify those specific gene substrates of FMRP, particularly those expressed in the brain , that are implicated in FXS progression. Moreover, we use...the co-localized R-loop formation and chromosome fragility in Fragile X cells, particularly at the brain -expressed genes, by ChIP-seq (detecting...X mental retardation protein February 2016, NGS Data Analysis & Informatics Conference, San Diego, California (Poster presentation) Title: Global

Brief Report: Aggression and Stereotypic Behavior in Males with Fragile X Syndrome-- Moderating Secondary Genes in a "Single Gene" Disorder

ERIC Educational Resources Information Center

Hessl, David; Tassone, Flora; Cordeiro, Lisa; Koldewyn, Kami; McCormick, Carolyn; Green, Cherie; Wegelin, Jacob; Yuhas, Jennifer; Hagerman, Randi J.

2008-01-01

Although fragile X syndrome (FXS) is a single gene disorder with a well-described phenotype, it is not known why some individuals develop more significant maladaptive behaviors such as aggression or autistic symptoms. Here, we studied two candidate genes known to affect mood and aggression, the serotonin transporter (5-HTTLPR) and monoamine…

A Longitudinal Follow-Up Study of Affect in Children and Adults with Cornelia de Lange Syndrome

ERIC Educational Resources Information Center

Nelson, Lisa; Moss, Jo; Oliver, Chris

2014-01-01

Studies of individuals with Cornelia de Lange syndrome (CdLS) have described changes in mood and behavior with age, although no empirical or longitudinal studies have been conducted. Caregivers of individuals with CdLS (N = 67), cri du chat syndrome (CdCS; N = 42), and Fragile X syndrome (FXS; N = 142) completed the Mood, Interest and Pleasure…

Finding mouse models of human lymphomas and leukemia's using the Jackson laboratory mouse tumor biology database.

PubMed

Begley, Dale A; Sundberg, John P; Krupke, Debra M; Neuhauser, Steven B; Bult, Carol J; Eppig, Janan T; Morse, Herbert C; Ward, Jerrold M

2015-12-01

Many mouse models have been created to study hematopoietic cancer types. There are over thirty hematopoietic tumor types and subtypes, both human and mouse, with various origins, characteristics and clinical prognoses. Determining the specific type of hematopoietic lesion produced in a mouse model and identifying mouse models that correspond to the human subtypes of these lesions has been a continuing challenge for the scientific community. The Mouse Tumor Biology Database (MTB; http://tumor.informatics.jax.org) is designed to facilitate use of mouse models of human cancer by providing detailed histopathologic and molecular information on lymphoma subtypes, including expertly annotated, on line, whole slide scans, and providing a repository for storing information on and querying these data for specific lymphoma models. Copyright © 2015 Elsevier Inc. All rights reserved.

Mouse models rarely mimic the transcriptome of human neurodegenerative diseases: A systematic bioinformatics-based critique of preclinical models.

PubMed

Burns, Terry C; Li, Matthew D; Mehta, Swapnil; Awad, Ahmed J; Morgan, Alexander A

2015-07-15

Translational research for neurodegenerative disease depends intimately upon animal models. Unfortunately, promising therapies developed using mouse models mostly fail in clinical trials, highlighting uncertainty about how well mouse models mimic human neurodegenerative disease at the molecular level. We compared the transcriptional signature of neurodegeneration in mouse models of Alzheimer׳s disease (AD), Parkinson׳s disease (PD), Huntington׳s disease (HD) and amyotrophic lateral sclerosis (ALS) to human disease. In contrast to aging, which demonstrated a conserved transcriptome between humans and mice, only 3 of 19 animal models showed significant enrichment for gene sets comprising the most dysregulated up- and down-regulated human genes. Spearman׳s correlation analysis revealed even healthy human aging to be more closely related to human neurodegeneration than any mouse model of AD, PD, ALS or HD. Remarkably, mouse models frequently upregulated stress response genes that were consistently downregulated in human diseases. Among potential alternate models of neurodegeneration, mouse prion disease outperformed all other disease-specific models. Even among the best available animal models, conserved differences between mouse and human transcriptomes were found across multiple animal model versus human disease comparisons, surprisingly, even including aging. Relative to mouse models, mouse disease signatures demonstrated consistent trends toward preserved mitochondrial function protein catabolism, DNA repair responses, and chromatin maintenance. These findings suggest a more complex and multifactorial pathophysiology in human neurodegeneration than is captured through standard animal models, and suggest that even among conserved physiological processes such as aging, mice are less prone to exhibit neurodegeneration-like changes. This work may help explain the poor track record of mouse-based translational therapies for neurodegeneration and provides a path forward to critically evaluate and improve animal models of human disease. Copyright © 2015 Elsevier B.V. All rights reserved.

Identification and Characterization of Novel FMRP-Associated miRNAs

DTIC Science & Technology

2014-12-01

further - primarily because of advantages of the approaches described below (Figures 6 and 7). We next tried FMRP antibody covalently crosslinked to...hands, crosslinked FMRP antibody did not always efficiently pull down FMRP from fly brain extract (as shown in Figure 3A) and inconsistently pulled...these goals has shed light on the molecular pathogenesis of FXS. Progress towards completion of aims: First, after significant setbacks developing novel

Daily Health Symptoms of Mothers of Adolescents and Adults with Fragile X Syndrome and Mothers of Adolescents and Adults with Autism Spectrum Disorder

ERIC Educational Resources Information Center

Smith, Leann E.; Seltzer, Marsha Mailick; Greenberg, Jan S.

2012-01-01

Health symptoms of mothers of adolescents and adults with fragile X syndrome (FXS; n = 112) were compared to a nationally-representative sample of mothers of similarly-aged children without disabilities (n = 230) as well as to a sample of mothers of adolescents and adults with autism spectrum disorders (ASD; n = 96). Health symptoms experienced in…

Treatment of Fragile X Syndrome with a Neuroactive Steroid

DTIC Science & Technology

2012-08-01

common form of inherited intellectual disability and autism . The protein (FMRP) encoded by the fragile X mental retardation gene (FMR1), is an RNA...FXS) is the most common inherited cause of mental retardation, and the most common single gene mutation associated with autism (Demark et al. 2003...profile of impairments, with the most interesting being comorbidity with autism . From the most recent studies, the prevalence of autism spectrum

Molecular Inconsistencies in a Fragile X Male with Early Onset Ataxia

PubMed Central

Hwang, Yun Tae; Dudding, Tracy; Aliaga, Solange Mabel; Arpone, Marta; Francis, David; Li, Xin; Slater, Howard Robert; Rogers, Carolyn; Bretherton, Lesley; du Sart, Desirée; Heard, Robert; Godler, David Eugeny

2016-01-01

Mosaicism for FMR1 premutation (PM: 55–199 CGG)/full mutation (FM: >200 CGG) alleles or the presence of unmethylated FM (UFM) have been associated with a less severe fragile X syndrome (FXS) phenotype and fragile X associated tremor/ataxia syndrome (FXTAS)—a late onset neurodegenerative disorder. We describe a 38 year old male carrying a 100% methylated FM detected with Southern blot (SB), which is consistent with complete silencing of FMR1 and a diagnosis of fragile X syndrome. However, his formal cognitive scores were not at the most severe end of the FXS phenotype and he displayed tremor and ataxic gait. With the association of UFM with FXTAS, we speculated that his ataxia might be related to an undetected proportion of UFM alleles. Such UFM alleles were confirmed by more sensitive PCR based methylation testing showing FM methylation between 60% and 70% in blood, buccal, and saliva samples and real-time PCR analysis showing incomplete silencing of FMR1. While he did not meet diagnostic criteria for FXTAS based on MRI findings, the underlying cause of his ataxia may be related to UFM alleles not detected by SB, and follow-up clinical and molecular assessment are justified if his symptoms worsen. PMID:27657133

Delayed stabilization of dendritic spines in fragile X mice.

PubMed

Cruz-Martín, Alberto; Crespo, Michelle; Portera-Cailliau, Carlos

2010-06-09

Fragile X syndrome (FXS) causes mental impairment and autism through transcriptional silencing of the Fmr1 gene, resulting in the loss of the RNA-binding protein fragile X mental retardation protein (FMRP). Cortical pyramidal neurons in affected individuals and Fmr1 knock-out (KO) mice have an increased density of dendritic spines. The mutant mice also show defects in synaptic and experience-dependent circuit plasticity, which are known to be mediated in part by dendritic spine dynamics. We used in vivo time-lapse imaging with two-photon microscopy through cranial windows in male and female neonatal mice to test the hypothesis that dynamics of dendritic protrusions are altered in KO mice during early postnatal development. We find that layer 2/3 neurons from wild-type mice exhibit a rapid decrease in dendritic spine dynamics during the first 2 postnatal weeks, as immature filopodia are replaced by mushroom spines. In contrast, KO mice show a developmental delay in the downregulation of spine turnover and in the transition from immature to mature spine subtypes. Blockade of metabotropic glutamate receptor (mGluR) signaling, which reverses some adult phenotypes of KO mice, accentuated this immature protrusion phenotype in KO mice. Thus, absence of FMRP delays spine stabilization and dysregulated mGluR signaling in FXS may partially normalize this early synaptic defect.

UNSTABLE MUTATIONS IN THE FMR1 GENE AND THE PHENOTYPES

PubMed Central

Loesch, Danuta; Hagerman, Randi

2014-01-01

Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable (‘dynamic’) mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene's promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethylated promoter (and thus, FMRP production), present a much less severe form of FXS. However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55-200) CGG expansions, termed ‘premutations’, which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, congnitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene's transcript (mRNA) is discussed. The next two sections are devoted to major and well defined clinical conditions associated with the premutation alleles. The first one is the late onset neurodegenerative disorder termed fragile X-associated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given. In the following section, the most recent findings concerning the possible contribution of FMR1 ‘grey zone’ alleles (those with the smallest repeat expansions overlapping with the normal range i.e., 41-54 CGGs), to the psychological and clinical manifestations, already associated with premutation alleles, are discussed. Special emphasis has been placed on the possibility that the modest elevation of ‘toxic’ FMR1 mRNA in the carriers of grey zone alleles may present an additional risk for some neurodegenerative diseases, such as those associated with parkinsonism, by synergizing with either other susceptibility genes or environmental poisons. The present status of the treatment of fragile X-related disorders, especially FXS, is presented in the last section of this chapter. Pharmacological interventions in this syndrome have recently extended beyond stimulants and antipsychotic medications, and the latest trials involving a group of GluR5 antagonists aim to ascertain if these substances have the potential to reverse some of the neurobiological abnormalities of FXS. PMID:23560306

System parameters for erythropoiesis control model: Comparison of normal values in human and mouse model

NASA Technical Reports Server (NTRS)

1979-01-01

The computer model for erythropoietic control was adapted to the mouse system by altering system parameters originally given for the human to those which more realistically represent the mouse. Parameter values were obtained from a variety of literature sources. Using the mouse model, the mouse was studied as a potential experimental model for spaceflight. Simulation studies of dehydration and hypoxia were performed. A comparison of system parameters for the mouse and human models is presented. Aside from the obvious differences expected in fluid volumes, blood flows and metabolic rates, larger differences were observed in the following: erythrocyte life span, erythropoietin half-life, and normal arterial pO2.

Human mammary microenvironment better regulates the biology of human breast cancer in humanized mouse model.

PubMed

Zheng, Ming-Jie; Wang, Jue; Xu, Lu; Zha, Xiao-Ming; Zhao, Yi; Ling, Li-Jun; Wang, Shui

2015-02-01

During the past decades, many efforts have been made in mimicking the clinical progress of human cancer in mouse models. Previously, we developed a human breast tissue-derived (HB) mouse model. Theoretically, it may mimic the interactions between "species-specific" mammary microenvironment of human origin and human breast cancer cells. However, detailed evidences are absent. The present study (in vivo, cellular, and molecular experiments) was designed to explore the regulatory role of human mammary microenvironment in the progress of human breast cancer cells. Subcutaneous (SUB), mammary fat pad (MFP), and HB mouse models were developed for in vivo comparisons. Then, the orthotopic tumor masses from three different mouse models were collected for primary culture. Finally, the biology of primary cultured human breast cancer cells was compared by cellular and molecular experiments. Results of in vivo mouse models indicated that human breast cancer cells grew better in human mammary microenvironment. Cellular and molecular experiments confirmed that primary cultured human breast cancer cells from HB mouse model showed a better proliferative and anti-apoptotic biology than those from SUB to MFP mouse models. Meanwhile, primary cultured human breast cancer cells from HB mouse model also obtained the migratory and invasive biology for "species-specific" tissue metastasis to human tissues. Comprehensive analyses suggest that "species-specific" mammary microenvironment of human origin better regulates the biology of human breast cancer cells in our humanized mouse model of breast cancer, which is more consistent with the clinical progress of human breast cancer.

Targeted Upregulation of FMRP Expression as an Approach to the Treatment of Fragile X Syndrome

DTIC Science & Technology

2016-10-01

Fragile X syndrome (FXS), the most common heritable form of intellectual disability and most common single-gene form of autism , is caused by partial...15. SUBJECT TERMS Fragile X, autism , FMR1, FXTAS, CGG repeat, epilepsy, seizures, FMRP, PTSD, premutation, iPSC, progenitor, calcium regulation...the most common heritable form of intellectual disability, the most common single-gene form of autism , and a relatively common cause of epilepsy

The Mouse Tumor Biology Database: A Comprehensive Resource for Mouse Models of Human Cancer.

PubMed

Krupke, Debra M; Begley, Dale A; Sundberg, John P; Richardson, Joel E; Neuhauser, Steven B; Bult, Carol J

2017-11-01

Research using laboratory mice has led to fundamental insights into the molecular genetic processes that govern cancer initiation, progression, and treatment response. Although thousands of scientific articles have been published about mouse models of human cancer, collating information and data for a specific model is hampered by the fact that many authors do not adhere to existing annotation standards when describing models. The interpretation of experimental results in mouse models can also be confounded when researchers do not factor in the effect of genetic background on tumor biology. The Mouse Tumor Biology (MTB) database is an expertly curated, comprehensive compendium of mouse models of human cancer. Through the enforcement of nomenclature and related annotation standards, MTB supports aggregation of data about a cancer model from diverse sources and assessment of how genetic background of a mouse strain influences the biological properties of a specific tumor type and model utility. Cancer Res; 77(21); e67-70. ©2017 AACR . ©2017 American Association for Cancer Research.

Drug discovery in prostate cancer mouse models.

PubMed

Valkenburg, Kenneth C; Pienta, Kenneth J

2015-01-01

The mouse is an important, though imperfect, organism with which to model human disease and to discover and test novel drugs in a preclinical setting. Many experimental strategies have been used to discover new biological and molecular targets in the mouse, with the hopes of translating these discoveries into novel drugs to treat prostate cancer in humans. Modeling prostate cancer in the mouse, however, has been challenging, and often drugs that work in mice have failed in human trials. The authors discuss the similarities and differences between mice and men; the types of mouse models that exist to model prostate cancer; practical questions one must ask when using a mouse as a model; and potential reasons that drugs do not often translate to humans. They also discuss the current value in using mouse models for drug discovery to treat prostate cancer and what needs are still unmet in field. With proper planning and following practical guidelines by the researcher, the mouse is a powerful experimental tool. The field lacks genetically engineered metastatic models, and xenograft models do not allow for the study of the immune system during the metastatic process. There remain several important limitations to discovering and testing novel drugs in mice for eventual human use, but these can often be overcome. Overall, mouse modeling is an essential part of prostate cancer research and drug discovery. Emerging technologies and better and ever-increasing forms of communication are moving the field in a hopeful direction.

Orthology for comparative genomics in the mouse genome database.

PubMed

Dolan, Mary E; Baldarelli, Richard M; Bello, Susan M; Ni, Li; McAndrews, Monica S; Bult, Carol J; Kadin, James A; Richardson, Joel E; Ringwald, Martin; Eppig, Janan T; Blake, Judith A

2015-08-01

The mouse genome database (MGD) is the model organism database component of the mouse genome informatics system at The Jackson Laboratory. MGD is the international data resource for the laboratory mouse and facilitates the use of mice in the study of human health and disease. Since its beginnings, MGD has included comparative genomics data with a particular focus on human-mouse orthology, an essential component of the use of mouse as a model organism. Over the past 25 years, novel algorithms and addition of orthologs from other model organisms have enriched comparative genomics in MGD data, extending the use of orthology data to support the laboratory mouse as a model of human biology. Here, we describe current comparative data in MGD and review the history and refinement of orthology representation in this resource.

[Informing members of families affected by fragile X syndrome of this diagnosis].

PubMed

Carrasco, M

2001-10-01

Fragile X syndrome (FXS) is a genetic disorder that may seriously affect the development of patients. One of the hardest tasks for the professionals of medicine is to tell the parents that their child is suffering a serious illness that may cause some permanent handicap. This normally implies drastic changes in live projects and expectations for the parents. The knowledge of diagnosis and the supply of information to the parents give rise to an important emotional impact on both parents and the rest of the family. In general terms, the patient implies more than a single ill person--a genetic illness such as FXS, which causes serious cognitive and behavioural disturbances, implies three situations that the family has to face: on one hand, the family has to accept a new world that had never been known; a son or daughter with a genetic disorder unknown not only for them, but also for most of the professionals they have visited before having a diagnosis, and in many cases with special needs and serious behavioural disturbances. On the other hand, the family must accept that the diagnosis may not be restricted to the patient, because some other members of the family could be suffering from the same illness. Finally, they have to face the fact that one of the parents has transmitted the illness, that is, 'the genetic guilt' in the illness of their son or daughter.

Genetically Engineered Mouse Models for Studying Inflammatory Bowel Disease

PubMed Central

Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

2015-01-01

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. PMID:26387641

Genome-wide expression profiling of five mouse models identifies similarities and differences with human psoriasis.

PubMed

Swindell, William R; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P; Voorhees, John J; Elder, James T; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P; DiGiovanni, John; Pittelkow, Mark R; Ward, Nicole L; Gudjonsson, Johann E

2011-04-04

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis.

Optimizing mouse models of neurodegenerative disorders: are therapeutics in sight?

PubMed

Lutz, Cathleen M; Osborne, Melissa A

2013-01-01

The genomic and biologic conservation between mice and humans, along with our increasing ability to manipulate the mouse genome, places the mouse as a premier model for deciphering disease mechanisms and testing potential new therapies. Despite these advantages, mouse models of neurodegenerative disease are sometimes difficult to generate and can present challenges that must be carefully addressed when used for preclinical studies. For those models that do exist, the standardization and optimization of the models is a critical step in ensuring success in both basic research and preclinical use. This review looks back on the history of model development for neurodegenerative diseases and highlights the key strategies that have been learned in order to improve the design, development and use of mouse models in the study of neurodegenerative disease.

Applications and Limitations of Mouse Models for Understanding Human Atherosclerosis

PubMed Central

von Scheidt, Moritz; Zhao, Yuqi; Kurt, Zeyneb; Pan, Calvin; Zeng, Lingyao; Yang, Xia; Schunkert, Heribert; Lusis, Aldons J.

2017-01-01

Most of the biological understanding of mechanisms underlying coronary artery disease (CAD) derives from studies of mouse models. The identification of multiple CAD loci and strong candidate genes in large human genome-wide association studies (GWAS) presented an opportunity to examine the relevance of mouse models for the human disease. We comprehensively reviewed the mouse literature, including 827 literature-derived genes, and compared it to human data. First, we observed striking concordance of risk factors for atherosclerosis in mice and humans. Second, there was highly significant overlap of mouse genes with human genes identified by GWAS. In particular, of the 46 genes with strong association signals in CAD-GWAS that were studied in mouse models all but one exhibited consistent effects on atherosclerosis-related phenotypes. Third, we compared 178 CAD-associated pathways derived from human GWAS with 263 from mouse studies and observed that over 50% were consistent between both species. PMID:27916529

Targeted Upregulation of FMRP Expression as an Approach to the Treatment of Fragile X Syndrome

DTIC Science & Technology

2015-08-01

form of autism, and a relatively common cause of epilepsy . The syndrome is caused by partial or complete silencing of the fragile X (FMR1) gene when...potential to correct ALL of the clinical domains of fragile X syndrome, including epilepsy -like activity observed for both those with FXS and carriers of...the FMR1 gene. 15. SUBJECT TERMS Fragile X, autism, FMR1, FXTAS, CGG repeat, epilepsy , seizures, FMRP, PTSD, premutation, iPSC, progenitor, calcium

Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome

DTIC Science & Technology

2017-10-01

AWARD NUMBER: W81XWH-15-1-0190 TITLE: Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome PRINCIPAL INVESTIGATOR: Dr...14 July 2017 4. TITLE AND SUBTITLE 5a. CONTRACT NUMBER Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome 5b. GRANT NUMBER...18 9. Appendices……………………………………………………………18 2 1. Introduction Fragile X syndrome (FXS) is the most common form of inherited

Genetically engineered mouse models for studying inflammatory bowel disease.

PubMed

Mizoguchi, Atsushi; Takeuchi, Takahito; Himuro, Hidetomo; Okada, Toshiyuki; Mizoguchi, Emiko

2016-01-01

Inflammatory bowel disease (IBD) is a chronic intestinal inflammatory condition that is mediated by very complex mechanisms controlled by genetic, immune, and environmental factors. More than 74 kinds of genetically engineered mouse strains have been established since 1993 for studying IBD. Although mouse models cannot fully reflect human IBD, they have provided significant contributions for not only understanding the mechanism, but also developing new therapeutic means for IBD. Indeed, 20 kinds of genetically engineered mouse models carry the susceptibility genes identified in human IBD, and the functions of some other IBD susceptibility genes have also been dissected out using mouse models. Cutting-edge technologies such as cell-specific and inducible knockout systems, which were recently employed to mouse IBD models, have further enhanced the ability of investigators to provide important and unexpected rationales for developing new therapeutic strategies for IBD. In this review article, we briefly introduce 74 kinds of genetically engineered mouse models that spontaneously develop intestinal inflammation. Copyright © 2015 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Mouse Tumor Biology (MTB): a database of mouse models for human cancer.

PubMed

Bult, Carol J; Krupke, Debra M; Begley, Dale A; Richardson, Joel E; Neuhauser, Steven B; Sundberg, John P; Eppig, Janan T

2015-01-01

The Mouse Tumor Biology (MTB; http://tumor.informatics.jax.org) database is a unique online compendium of mouse models for human cancer. MTB provides online access to expertly curated information on diverse mouse models for human cancer and interfaces for searching and visualizing data associated with these models. The information in MTB is designed to facilitate the selection of strains for cancer research and is a platform for mining data on tumor development and patterns of metastases. MTB curators acquire data through manual curation of peer-reviewed scientific literature and from direct submissions by researchers. Data in MTB are also obtained from other bioinformatics resources including PathBase, the Gene Expression Omnibus and ArrayExpress. Recent enhancements to MTB improve the association between mouse models and human genes commonly mutated in a variety of cancers as identified in large-scale cancer genomics studies, provide new interfaces for exploring regions of the mouse genome associated with cancer phenotypes and incorporate data and information related to Patient-Derived Xenograft models of human cancers. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

The latest animal models of ovarian cancer for novel drug discovery.

PubMed

Magnotti, Elizabeth; Marasco, Wayne A

2018-03-01

Epithelial ovarian cancer is a heterogeneous disease classified into five subtypes, each with a different molecular profile. Most cases of ovarian cancer are diagnosed after metastasis of the primary tumor and are resistant to traditional platinum-based chemotherapeutics. Mouse models of ovarian cancer have been utilized to discern ovarian cancer tumorigenesis and the tumor's response to therapeutics. Areas covered: The authors provide a review of mouse models currently employed to understand ovarian cancer. This article focuses on advances in the development of orthotopic and patient-derived tumor xenograft (PDX) mouse models of ovarian cancer and discusses current humanized mouse models of ovarian cancer. Expert opinion: The authors suggest that humanized mouse models of ovarian cancer will provide new insight into the role of the human immune system in combating and augmenting ovarian cancer and aid in the development of novel therapeutics. Development of humanized mouse models will take advantage of the NSG and NSG-SGM3 strains of mice as well as new strains that are actively being derived.

How Genetically Engineered Mouse Tumor Models Provide Insights Into Human Cancers

PubMed Central

Politi, Katerina; Pao, William

2011-01-01

Genetically engineered mouse models (GEMMs) of human cancer were first created nearly 30 years ago. These early transgenic models demonstrated that mouse cells could be transformed in vivo by expression of an oncogene. A new field emerged, dedicated to generating and using mouse models of human cancer to address a wide variety of questions in cancer biology. The aim of this review is to highlight the contributions of mouse models to the diagnosis and treatment of human cancers. Because of the breadth of the topic, we have selected representative examples of how GEMMs are clinically relevant rather than provided an exhaustive list of experiments. Today, as detailed here, sophisticated mouse models are being created to study many aspects of cancer biology, including but not limited to mechanisms of sensitivity and resistance to drug treatment, oncogene cooperation, early detection, and metastasis. Alternatives to GEMMs, such as chemically induced or spontaneous tumor models, are not discussed in this review. PMID:21263096

Integrating model behavior, optimization, and sensitivity/uncertainty analysis: overview and application of the MOUSE software toolbox

USDA-ARS?s Scientific Manuscript database

This paper provides an overview of the Model Optimization, Uncertainty, and SEnsitivity Analysis (MOUSE) software application, an open-source, Java-based toolbox of visual and numerical analysis components for the evaluation of environmental models. MOUSE is based on the OPTAS model calibration syst...

Disrupting the male germ line to find infertility and contraception targets.

PubMed

Archambeault, Denise R; Matzuk, Martin M

2014-05-01

Genetically-manipulated mouse models have become indispensible for broadening our understanding of genes and pathways related to male germ cell development. Until suitable in vitro systems for studying spermatogenesis are perfected, in vivo models will remain the gold standard for inquiry into testicular function. Here, we discuss exciting advances that are allowing researchers faster, easier, and more customizable access to their mouse models of interest. Specifically, the trans-NIH Knockout Mouse Project (KOMP) is working to generate knockout mouse models of every gene in the mouse genome. The related Knockout Mouse Phenotyping Program (KOMP2) is performing systematic phenotypic analysis of this genome-wide collection of knockout mice, including fertility screening. Together, these programs will not only uncover new genes involved in male germ cell development but also provide the research community with the mouse models necessary for further investigations. In addition to KOMP/KOMP2, another promising development in the field of mouse models is the advent of CRISPR (clustered regularly interspaced short palindromic repeat)-Cas technology. Utilizing 20 nucleotide guide sequences, CRISPR/Cas has the potential to introduce sequence-specific insertions, deletions, and point mutations to produce null, conditional, activated, or reporter-tagged alleles. CRISPR/Cas can also successfully target multiple genes in a single experimental step, forgoing the multiple generations of breeding traditionally required to produce mouse models with deletions, insertions, or mutations in multiple genes. In addition, CRISPR/Cas can be used to create mouse models carrying variants identical to those identified in infertile human patients, providing the opportunity to explore the effects of such mutations in an in vivo system. Both the KOMP/KOMP2 projects and the CRISPR/Cas system provide powerful, accessible genetic approaches to the study of male germ cell development in the mouse. A more complete understanding of male germ cell biology is critical for the identification of novel targets for potential non-hormonal contraceptive intervention. Copyright © 2014. Published by Elsevier Masson SAS.

Genome-Wide Expression Profiling of Five Mouse Models Identifies Similarities and Differences with Human Psoriasis

PubMed Central

Swindell, William R.; Johnston, Andrew; Carbajal, Steve; Han, Gangwen; Wohn, Christian; Lu, Jun; Xing, Xianying; Nair, Rajan P.; Voorhees, John J.; Elder, James T.; Wang, Xiao-Jing; Sano, Shigetoshi; Prens, Errol P.; DiGiovanni, John; Pittelkow, Mark R.; Ward, Nicole L.; Gudjonsson, Johann E.

2011-01-01

Development of a suitable mouse model would facilitate the investigation of pathomechanisms underlying human psoriasis and would also assist in development of therapeutic treatments. However, while many psoriasis mouse models have been proposed, no single model recapitulates all features of the human disease, and standardized validation criteria for psoriasis mouse models have not been widely applied. In this study, whole-genome transcriptional profiling is used to compare gene expression patterns manifested by human psoriatic skin lesions with those that occur in five psoriasis mouse models (K5-Tie2, imiquimod, K14-AREG, K5-Stat3C and K5-TGFbeta1). While the cutaneous gene expression profiles associated with each mouse phenotype exhibited statistically significant similarity to the expression profile of psoriasis in humans, each model displayed distinctive sets of similarities and differences in comparison to human psoriasis. For all five models, correspondence to the human disease was strong with respect to genes involved in epidermal development and keratinization. Immune and inflammation-associated gene expression, in contrast, was more variable between models as compared to the human disease. These findings support the value of all five models as research tools, each with identifiable areas of convergence to and divergence from the human disease. Additionally, the approach used in this paper provides an objective and quantitative method for evaluation of proposed mouse models of psoriasis, which can be strategically applied in future studies to score strengths of mouse phenotypes relative to specific aspects of human psoriasis. PMID:21483750

[Effect of topical application of a recombinant adenovirus carrying promyelocytic leukemia gene in a psoriasis-like mouse model].

PubMed

Wang, Qiongyu; Zhang, Aijun; Ma, Huiqun; Wang, Shijie; Ma, Yunyun; Zou, Xingwei; Li, Ruilian

2013-03-01

To investigate the effects of topical treatment with adenovirus-mediated promyelocytic leukemia gene (PML) gene in a psoriasis-like mouse model. The effect of adenovirus-mediated PML gene on the granular layer of mouse tail scale epidermis and epithelial mitosis were observed on longitudinal histological sections prepared from the tail skin and vaginal epithelium of the mice. Adenovirus-mediated PML gene significantly inhibited mitosis of mouse vaginal epithelial cells and promoted the formation of granular layer in mouse tail scale epidermis. The therapeutic effect of PML gene in the psoriasis-like mouse model may be associated with increased granular cells and suppressed epidemic cell proliferation.

Generation of transgenic mouse model using PTTG as an oncogene.

PubMed

Kakar, Sham S; Kakar, Cohin

2015-01-01

The close physiological similarity between the mouse and human has provided tools to understanding the biological function of particular genes in vivo by introduction or deletion of a gene of interest. Using a mouse as a model has provided a wealth of resources, knowledge, and technology, helping scientists to understand the biological functions, translocation, trafficking, and interaction of a candidate gene with other intracellular molecules, transcriptional regulation, posttranslational modification, and discovery of novel signaling pathways for a particular gene. Most importantly, the generation of the mouse model for a specific human disease has provided a powerful tool to understand the etiology of a disease and discovery of novel therapeutics. This chapter describes in detail the step-by-step generation of the transgenic mouse model, which can be helpful in guiding new investigators in developing successful models. For practical purposes, we will describe the generation of a mouse model using pituitary tumor transforming gene (PTTG) as the candidate gene of interest.

What Is the Predictive Value of Animal Models for Vaccine Efficacy in Humans? Reevaluating the Potential of Mouse Models for the Human Immune System.

PubMed

Jameson, Stephen C; Masopust, David

2018-04-02

Much of what we understand about immunology, including the response to vaccines, come from studies in mice because they provide many practical advantages compared with research in higher mammals and humans. Nevertheless, modalities for preventing or treating disease do not always translate from mouse to humans, which has led to increasing scrutiny of the continued merits of mouse research. Here, we summarize the pros and cons of current laboratory mouse models for immunology research and discuss whether overreliance on nonphysiological, ultra-hygienic animal husbandry approaches has limited the ultimate translation potential of mouse-derived data to humans. Alternative approaches are discussed that may extend the use of the mouse model for preclinical studies. Copyright © 2018 Cold Spring Harbor Laboratory Press; all rights reserved.

Mouse Models in Bone Marrow Transplantation and Adoptive Cellular Therapy

PubMed Central

Arber, Caroline; Brenner, Malcolm K.; Reddy, Pavan

2014-01-01

Mouse models of transplantation have been indispensable to the development of bone marrow transplantation (BMT). Their role in the generation of basic science knowledge is invaluable and is subject to discussion below. However, this article focuses on the direct role and relevance of mouse models towards the clinical development and advances in BMT and adoptive T-cell therapy for human diseases. The authors aim to present a thoughtful perspective on the pros and cons of mouse models while noting that despite imperfections these models are obligatory for the development of science-based medicine. PMID:24216170

Fmrp Interacts with Adar and Regulates RNA Editing, Synaptic Density and Locomotor Activity in Zebrafish

PubMed Central

Porath, Hagit T.; Barak, Michal; Pinto, Yishay; Wachtel, Chaim; Zilberberg, Alona; Lerer-Goldshtein, Tali; Efroni, Sol; Levanon, Erez Y.; Appelbaum, Lior

2015-01-01

Fragile X syndrome (FXS) is the most frequent inherited form of mental retardation. The cause for this X-linked disorder is the silencing of the fragile X mental retardation 1 (fmr1) gene and the absence of the fragile X mental retardation protein (Fmrp). The RNA-binding protein Fmrp represses protein translation, particularly in synapses. In Drosophila, Fmrp interacts with the adenosine deaminase acting on RNA (Adar) enzymes. Adar enzymes convert adenosine to inosine (A-to-I) and modify the sequence of RNA transcripts. Utilizing the fmr1 zebrafish mutant (fmr1-/-), we studied Fmrp-dependent neuronal circuit formation, behavior, and Adar-mediated RNA editing. By combining behavior analyses and live imaging of single axons and synapses, we showed hyperlocomotor activity, as well as increased axonal branching and synaptic density, in fmr1-/- larvae. We identified thousands of clustered RNA editing sites in the zebrafish transcriptome and showed that Fmrp biochemically interacts with the Adar2a protein. The expression levels of the adar genes and Adar2 protein increased in fmr1-/- zebrafish. Microfluidic-based multiplex PCR coupled with deep sequencing showed a mild increase in A-to-I RNA editing levels in evolutionarily conserved neuronal and synaptic Adar-targets in fmr1-/- larvae. These findings suggest that loss of Fmrp results in increased Adar-mediated RNA editing activity on target-specific RNAs, which, in turn, might alter neuronal circuit formation and behavior in FXS. PMID:26637167

Fragile X spectrum disorders.

PubMed

Lozano, Reymundo; Rosero, Carolina Alba; Hagerman, Randi J

2014-11-01

The fragile X mental retardation 1 gene (FMR1), which codes for the fragile X mental retardation 1 protein (FMRP), is located at Xp27.3. The normal allele of the FMR1 gene typically has 5 to 40 CGG repeats in the 5' untranslated region; abnormal alleles of dynamic mutations include the full mutation (> 200 CGG repeats), premutation (55-200 CGG repeats) and the gray zone mutation (45-54 CGG repeats). Premutation carriers are common in the general population with approximately 1 in 130-250 females and 1 in 250-810 males, whereas the full mutation and Fragile X syndrome (FXS) occur in approximately 1 in 4000 to 1 in 7000. FMR1 mutations account for a variety of phenotypes including the most common monogenetic cause of inherited intellectual disability (ID) and autism (FXS), the most common genetic form of ovarian failure, the fragile X-associated primary ovarian insufficiency (FXPOI, premutation); and fragile X-associated tremor/ataxia syndrome (FXTAS, premutation). The premutation can also cause developmental problems including ASD and ADHD especially in boys and psychopathology including anxiety and depression in children and adults. Some premutation carriers can have a deficit of FMRP and some unmethylated full mutation individuals can have elevated FMR1 mRNA that is considered a premutation problem. Therefore the term "Fragile X Spectrum Disorder" (FXSD) should be used to include the wide range of overlapping phenotypes observed in affected individuals with FMR1 mutations. In this review we focus on the phenotypes and genotypes of children with FXSD.

A 15-year-long Southern blotting analysis of FMR1 to detect female carriers and for prenatal diagnosis of fragile X syndrome in Taiwan.

PubMed

Tzeng, C-C; Tsai, L-P; Chang, Y-K; Hung, Y-J; Chang, Y-Y; Su, Y-P; Jiang, J-J; Liang, H-M

2017-08-01

Here, we review the results of Southern blotting analyses of the FMR1 gene performed in our reference laboratory in Taiwan over a 15-year period. In total, 725 high-risk women with a family history of fragile X syndrome (FXS) or idiopathic intellectual disability, 3911 low-risk pregnant women without such family history, and prenatal diagnosis data for 32 foetuses from 24 carrier mothers were included. Only 2 carriers were in the low-risk group, which indicated a prevalence of 1 of 1955 women (95% confidence interval: 1/7156-1/539). A total of 100 carriers were found to be in the high-risk group, thus revealing a significantly higher frequency than the low-risk group (100/725 vs 2/3911, P<0.0001). Eight of the 14 foetuses that inherited the maternal mutant allele were verified to have a full mutation, with the smallest maternal pre-mutation allele carrying 56 CGG repeats. The overall findings confirmed that the carrier prevalence among low-risk women in Taiwan is significantly lower than that reported in western countries. Therefore, the most important step for preventing FXS in Taiwan would be to focus on high-risk women by promoting general awareness of this disease and spreading knowledge regarding the benefits of carrier screening and prenatal testing. © 2017 John Wiley & Sons A/S. Published by John Wiley & Sons Ltd.

Fragile X Premutation Carrier Epidemiology and Symptomatology in Israel-Results from a Tertiary Child Developmental Center.

PubMed

Gabis, Lidia V; Gruber, Noah; Berkenstadt, Michal; Shefer, Shahar; Attia, Odelia Leon; Mula, Dana; Cohen, Yoram; Elizur, Shai E

2016-10-01

Fragile X syndrome (FXS) is the most prevalent known genetically inherited cause for autism and intellectual disability. Premutation state can cause several clinical disorders as well. We aimed to perform a nesting approach to acquire data with regard to first degree relatives of index fragile X cases at the largest child development center in Israel in order to map characteristics of Israeli FXS permutation women carriers. Seventy-nine women were referred due to a related fragile X syndrome patient, mainly an offspring or sibling. General information regarding demographics, ethnicity, and associated medical conditions were collected using interviews and structured questionnaires. Thirteen (17 %) of the women who were referred as "carrier" were proven to be actually full mutation. The mean years of education were 14 (±1.51, range 12-17). Twenty-one women (27 %) originated from Tunisia (mainly from the island of Djerba). Ten women (13 %) reported delivery of their affected offspring beyond 41 gestational weeks. Twenty-two percent of women with premutation reported symptoms consistent with learning difficulties, mainly dyscalculia, and 14 % reported ADHD symptoms. Awareness about clinical disorders of the carriers was existent only in 25 % of the patients. Increased awareness and knowledge dissemination concerning premutation symptomatology and associated medical conditions are warranted. We suggest a national registry to be installed in different countries in order to identify fragile X premutation carriers at increased risk for various medical complications.

Centralized mouse repositories.

PubMed

Donahue, Leah Rae; Hrabe de Angelis, Martin; Hagn, Michael; Franklin, Craig; Lloyd, K C Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T

2012-10-01

Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world.

Centralized Mouse Repositories

PubMed Central

Donahue, Leah Rae; de Angelis, Martin Hrabe; Hagn, Michael; Franklin, Craig; Lloyd, K. C. Kent; Magnuson, Terry; McKerlie, Colin; Nakagata, Naomi; Obata, Yuichi; Read, Stuart; Wurst, Wolfgang; Hörlein, Andreas; Davisson, Muriel T.

2013-01-01

Because the mouse is used so widely for biomedical research and the number of mouse models being generated is increasing rapidly, centralized repositories are essential if the valuable mouse strains and models that have been developed are to be securely preserved and fully exploited. Ensuring the ongoing availability of these mouse strains preserves the investment made in creating and characterizing them and creates a global resource of enormous value. The establishment of centralized mouse repositories around the world for distributing and archiving these resources has provided critical access to and preservation of these strains. This article describes the common and specialized activities provided by major mouse repositories around the world. PMID:22945696

Fragile X mental retardation protein has a unique, evolutionarily conserved neuronal function not shared with FXR1P or FXR2P

PubMed Central

Coffee, R. Lane; Tessier, Charles R.; Woodruff, Elvin A.; Broadie, Kendal

2010-01-01

SUMMARY Fragile X syndrome (FXS), resulting solely from the loss of function of the human fragile X mental retardation 1 (hFMR1) gene, is the most common heritable cause of mental retardation and autism disorders, with syndromic defects also in non-neuronal tissues. In addition, the human genome encodes two closely related hFMR1 paralogs: hFXR1 and hFXR2. The Drosophila genome, by contrast, encodes a single dFMR1 gene with close sequence homology to all three human genes. Drosophila that lack the dFMR1 gene (dfmr1 null mutants) recapitulate FXS-associated molecular, cellular and behavioral phenotypes, suggesting that FMR1 function has been conserved, albeit with specific functions possibly sub-served by the expanded human gene family. To test evolutionary conservation, we used tissue-targeted transgenic expression of all three human genes in the Drosophila disease model to investigate function at (1) molecular, (2) neuronal and (3) non-neuronal levels. In neurons, dfmr1 null mutants exhibit elevated protein levels that alter the central brain and neuromuscular junction (NMJ) synaptic architecture, including an increase in synapse area, branching and bouton numbers. Importantly, hFMR1 can, comparably to dFMR1, fully rescue both the molecular and cellular defects in neurons, whereas hFXR1 and hFXR2 provide absolutely no rescue. For non-neuronal requirements, we assayed male fecundity and testes function. dfmr1 null mutants are effectively sterile owing to disruption of the 9+2 microtubule organization in the sperm tail. Importantly, all three human genes fully and equally rescue mutant fecundity and spermatogenesis defects. These results indicate that FMR1 gene function is evolutionarily conserved in neural mechanisms and cannot be compensated by either FXR1 or FXR2, but that all three proteins can substitute for each other in non-neuronal requirements. We conclude that FMR1 has a neural-specific function that is distinct from its paralogs, and that the unique FMR1 function is responsible for regulating neuronal protein expression and synaptic connectivity. PMID:20442204

Phosphorylation of FMRP and alterations of FMRP complex underlie enhanced mLTD in adult rats triggered by early life seizures.

PubMed

Bernard, Paul B; Castano, Anna M; O'Leary, Heather; Simpson, Kameron; Browning, Michael D; Benke, Tim A

2013-11-01

Outside of Fragile X syndrome (FXS), the role of Fragile-X Mental Retardation Protein (FMRP) in mediating neuropsychological abnormalities is not clear. FMRP, p70-S6 kinase (S6K) and protein phosphatase 2A (PP2A) are thought to cooperate as a dynamic signaling complex. In our prior work, adult rats have enhanced CA1 hippocampal long-term depression (LTD) following an early life seizure (ELS). We now show that mGluR-mediated LTD (mLTD) is specifically enhanced following ELS, similar to FMRP knock-outs. Total FMRP expression is unchanged but S6K is hyperphosphorylated, consistent with S6K overactivation. We postulated that either disruption of the FMRP-S6K-PP2A complex and/or removal of this complex from synapses could explain our findings. Using subcellular fractionation, we were surprised to find that concentrations of FMRP and PP2A were undisturbed in the synaptosomal compartment but reduced in parallel in the cytosolic compartment. Following ELS FMRP phosphorylation was reduced in the cytosolic compartment and increased in the synaptic compartment, in parallel with the compartmentalization of S6K activation. Furthermore, FMRP and PP2A remain bound following ELS. In contrast, the interaction of S6K with FMRP is reduced by ELS. Blockade of PP2A results in enhanced mLTD; this is occluded by ELS. This suggests a critical role for the location and function of the FMRP-S6K-PP2A signaling complex in limiting the amount of mLTD. Specifically, non-synaptic targeting and the function of the complex may influence the "set-point" for regulating mLTD. Consistent with this, striatal-enriched protein tyrosine phosphatase (STEP), an FMRP "target" which regulates mLTD expression, is specifically increased in the synaptosomal compartment following ELS. Further, we provide behavioral data to suggest that FMRP complex dysfunction may underlie altered socialization, a symptom associated and observed in other rodent models of autism, including FXS. © 2013.

Molecular Indicators of Stress-Induced Neuroinflammation in a Mouse Model Simulating Features of Post-Traumatic Stress Disorder (Open Access)

DTIC Science & Technology

2017-05-23

OPEN ORIGINAL ARTICLE Molecular indicators of stress-induced neuroinflammation in a mouse model simulating features of post -traumatic stress disorder... post -traumatic stress disorder (PTSD). The model involved exposure of an intruder (male C57BL/6) mouse to a resident aggressor (male SJL) mouse for 5...revealed that neurogenesis and synaptic plasticity pathways were activated during the early responses but were inhibited after the later post -trauma

Genetic characterization and improved genotyping of the dysferlin-deficient mouse strain Dysf (tm1Kcam).

PubMed

Wiktorowicz, Tatiana; Kinter, Jochen; Kobuke, Kazuhiro; Campbell, Kevin P; Sinnreich, Michael

2015-01-01

Mouse models of dysferlinopathies are valuable tools with which to investigate the pathomechanisms underlying these diseases and to test novel therapeutic strategies. One such mouse model is the Dysf (tm1Kcam) strain, which was generated using a targeting vector to replace a 12-kb region of the dysferlin gene and which features a progressive muscular dystrophy. A prerequisite for successful animal studies using genetic mouse models is an accurate genotyping protocol. Unfortunately, the lack of robustness of currently available genotyping protocols for the Dysf (tm1Kcam) mouse has prevented efficient colony management. Initial attempts to improve the genotyping protocol based on the published genomic structure failed. These difficulties led us to analyze the targeted locus of the dysferlin gene of the Dysf (tm1Kcam) mouse in greater detail. In this study we resequenced and analyzed the targeted locus of the Dysf (tm1Kcam) mouse and developed a novel PCR protocol for genotyping. We found that instead of a deletion, the dysferlin locus in the Dysf (tm1Kcam) mouse carries a targeted insertion. This genetic characterization enabled us to establish a reliable method for genotyping of the Dysf (tm1Kcam) mouse, and thus has made efficient colony management possible. Our work will make the Dysf (tm1Kcam) mouse model more attractive for animal studies of dysferlinopathies.

Mouse models of neurodegenerative diseases: criteria and general methodology.

PubMed

Janus, Christopher; Welzl, Hans

2010-01-01

The major symptom of Alzheimer's disease is rapidly progressing dementia, coinciding with the formation of amyloid and tau deposits in the central nervous system, and neuronal death. At present familial cases of dementias provide the most promising foundation for modelling neurodegeneration. We describe the mnemonic and other major behavioral symptoms of tauopathies, briefly outline the genetics underlying familiar cases and discuss the arising implications for modelling the disease in mostly transgenic mouse lines. We then depict to what degree the most recent mouse models replicate pathological and cognitive characteristics observed in patients.There is no universally valid behavioral test battery to evaluate mouse models. The selection of individual tests depends on the behavioral and/or memory system in focus, the type of a model and how well it replicates the pathology of a disease and the amount of control over the genetic background of the mouse model. However it is possible to provide guidelines and criteria for modelling the neurodegeneration, setting up the experiments and choosing relevant tests. One should not adopt a "one (trans)gene, one disease" interpretation, but should try to understand how the mouse genome copes with the protein expression of the transgene in question. Further, it is not possible to recommend some mouse models over others since each model is valuable within its own constraints, and the way experiments are performed often reflects the idiosyncratic reality of specific laboratories. Our purpose is to improve bridging molecular and behavioural approaches in translational research.

Direct comparison of the pharmacodynamics of four antifungal drugs in a mouse model of disseminated candidiasis using microbiological assays of serum drug concentrations.

PubMed

Maki, Katsuyuki; Holmes, Ann R; Watabe, Etsuko; Iguchi, Yumi; Matsumoto, Satoru; Ikeda, Fumiaki; Tawara, Shuichi; Mutoh, Seitaro

2007-01-01

The aim of this study was to compare the pharmacodynamics of the azole antifungal drugs fluconazole, itraconazole and ketoconazole, and the polyene antifungal amphotericin B, in a mouse model of disseminated Candida albicans infection. In order to directly compare effective serum concentrations of these antifungals, drug concentrations were assayed microbiologically by measuring inhibition of C. albicans mycelial growth (mMIC) in a mouse serum-based assay (serum antifungal titer). Efficacy in the mouse infection model was determined using an organ-based (kidney burden) endpoint. For all four drugs, the serum antifungal titers, 8 hr after administration of single doses of drugs at a range of drug concentrations, correlated closely with C. albicans kidney fungal burden in the mouse model. The results showed that determining serum antifungal titer may be used to accurately represent kidney fungal burden in a mouse model of disseminated candidiasis and allowed direct comparison of the pharmacodynamics of differing classes of antifungal drugs.

Mouse Models as Tools to Identify Genetic Pathways for Retinal Degeneration, as Exemplified by Leber's Congenital Amaurosis.

PubMed

Chang, Bo

2016-01-01

Leber's congenital amaurosis (LCA) is an inherited retinal degenerative disease characterized by severe loss of vision in the first year of life. In addition to early vision loss, a variety of other eye-related abnormalities including roving eye movements, deep-set eyes, and sensitivity to bright light also occur with this disease. Many animal models of LCA are available and the study them has led to a better understanding of the pathology of the disease, and has led to the development of therapeutic strategies aimed at curing or slowing down LCA. Mouse models, with their well-developed genetics and similarity to human physiology and anatomy, serve as powerful tools with which to investigate the etiology of human LCA. Such mice provide reproducible, experimental systems for elucidating pathways of normal development, function, designing strategies and testing compounds for translational research and gene-based therapies aimed at delaying the diseases progression. In this chapter, I describe tools used in the discovery and evaluation of mouse models of LCA including a Phoenix Image-Guided Optical Coherence Tomography (OCT) and a Diagnosys Espion Visual Electrophysiology System. Three mouse models are described, the rd3 mouse model for LCA12 and LCA1, the rd12 mouse model for LCA2, and the rd16 mouse model for LCA10.

Differences in Pathogenesis for Salmonella enterica serovar Typhimurium in the Mouse Versus the Swine Model Identify Bacterial Gene Products Required for Systemic but not Gastrointestinal Disease

USDA-ARS?s Scientific Manuscript database

Over the last several decades, the mouse model of Typhoid fever has been an extremely productive model to investigate Salmonella enterica serovar Typhimurium pathogenesis. The mouse is the paradigm for investigating systemic disease due to infection by Salmonella; however, the swine model of gastro...

A unified model of the excitability of mouse sensory and motor axons.

PubMed

Makker, Preet G S; Matamala, José Manuel; Park, Susanna B; Lees, Justin G; Kiernan, Matthew C; Burke, David; Moalem-Taylor, Gila; Howells, James

2018-06-19

Non-invasive nerve excitability techniques have provided valuable insight into the understanding of neurological disorders. The widespread use of mice in translational research on peripheral nerve disorders and by pharmaceutical companies during drug development requires valid and reliable models that can be compared to humans. This study established a novel experimental protocol that enables comparative assessment of the excitability properties of motor and sensory axons at the same site in mouse caudal nerve, compared the mouse data to data for motor and sensory axons in human median nerve at the wrist, and constructed a mathematical model of the excitability of mouse axons. In a separate study, ischaemia was employed as an experimental manoeuvre to test the translational utility of this preparation. The patterns of mouse sensory and motor excitability were qualitatively similar to human studies under normal and ischaemic conditions. The most conspicuous differences between mouse and human studies were observed in the recovery cycle and the response to hyperpolarization. Modelling showed that an increase in temperature in mouse axons could account for most of the differences in the recovery cycle. The modelling also suggested a larger hyperpolarization-activated conductance in mouse axons. The kinetics of this conductance appeared to be much slower raising the possibility that an additional or different hyperpolarization-activated cyclic-nucleotide gated (HCN) channel isoform underlies the accommodation to hyperpolarization in mouse axons. Given a possible difference in HCN isoforms, caution should be exercised in extrapolating from studies of mouse motor and sensory axons to human nerve disorders. This article is protected by copyright. All rights reserved.

Rapamycin improves sociability in the BTBR T(+)Itpr3(tf)/J mouse model of autism spectrum disorders.

PubMed

Burket, Jessica A; Benson, Andrew D; Tang, Amy H; Deutsch, Stephen I

2014-01-01

Overactivation of the mammalian target of rapamycin (mTOR) has been implicated in the pathogenesis of syndromic forms of autism spectrum disorders (ASDs), such as tuberous sclerosis complex, neurofibromatosis 1, and fragile X syndrome. Administration of mTORC1 (mTOR complex 1) inhibitors (e.g. rapamycin) in syndromic mouse models of ASDs improved behavior, cognition, and neuropathology. However, since only a minority of ASDs are due to the effects of single genes (∼10%), there is a need to explore inhibition of mTOR activity in mouse models that may be more relevant to the majority of nonsyndromic presentations, such as the genetically inbred BTBR T(+)Itpr3(tf)/J (BTBR) mouse model of ASDs. BTBR mice have social impairment and exhibit increased stereotypic behavior. In prior work, d-cycloserine, a partial glycineB site agonist that targets the N-methyl-d-aspartate (NMDA) receptor, was shown to improve sociability in both Balb/c and BTBR mouse models of ASDs. Importantly, NMDA receptor activation regulates mTOR signaling activity. The current study investigated the ability of rapamycin (10mg/kg, i.p.×four days), an mTORC1 inhibitor, to improve sociability and stereotypic behavior in BTBR mice. Using a standard paradigm to assess mouse social behavior, rapamycin improved several measures of sociability in the BTBR mouse, suggesting that mTOR overactivation represents a therapeutic target that mediates or contributes to impaired sociability in the BTBR mouse model of ASDs. Interestingly, there was no effect of rapamycin on stereotypic behaviors in this mouse model. Copyright © 2013 Elsevier Inc. All rights reserved.

In Vivo Hyperthermic Stress Model: An Easy Tool to Study the Effects of Oxidative Stress on Neuronal Tau Functionality in Mouse Brain.

PubMed

Chauderlier, Alban; Delattre, Lucie; Buée, Luc; Galas, Marie-Christine

2017-01-01

Oxidative damage is an early event in neurodegenerative disorders such as Alzheimer disease. To increase oxidative stress in AD-related mouse models is essential to study early mechanisms involved in the physiopathology of these diseases. In this chapter, we describe an experimental mouse model of transient and acute hyperthermic stress to induce in vivo an increase of oxidative stress in the brain of any kind of wild-type or transgenic mouse.

Implementation of a manual for working with wobbler mice and criteria for discontinuation of the experiment.

PubMed

Ott, Bastian; Dahlke, Carolin; Meller, Karl; Napirei, Markus; Schmitt-John, Thomas; Brand-Saberi, Beate; Theiss, Carsten; Saberi, Darius

2015-07-01

Mouse breeding is of importance to a whole range of medical and biological research. There are many known mouse models for motor neuron diseases. However, it must be kept in mind that especially mouse models for amyotrophic lateral sclerosis develop severe symptoms causing intense stress. This article is designed to summarize conscientious work with the wobbler mouse, a model for the sporadic form of amyotrophic lateral sclerosis. This mouse model is characterized by a degeneration of α-motor-neurons leading to head tremor, loss of body weight and rapidly progressive paralysis. Although this mouse model has been known since 1956, there are no guidelines for breeding wobbler mice. Due to the lack of such guidelines the present study tries to close this gap and implements a manual for further studies. It includes the whole workflow in regard to wobbler mice from breeding and animal care taking, genotyping and phenotype analysis, but also gives some examples for the use of various neuronal tissues for histological investigation. Beside the progress in research a second aim should always be the enhancement of mouse welfare and reduction of stress for the laboratory animals. Copyright © 2015 Elsevier GmbH. All rights reserved.

Rational Design of Mouse Models for Cancer Research.

PubMed

Landgraf, Marietta; McGovern, Jacqui A; Friedl, Peter; Hutmacher, Dietmar W

2018-03-01

The laboratory mouse is widely considered as a valid and affordable model organism to study human disease. Attempts to improve the relevance of murine models for the investigation of human pathologies led to the development of various genetically engineered, xenograft and humanized mouse models. Nevertheless, most preclinical studies in mice suffer from insufficient predictive value when compared with cancer biology and therapy response of human patients. We propose an innovative strategy to improve the predictive power of preclinical cancer models. Combining (i) genomic, tissue engineering and regenerative medicine approaches for rational design of mouse models with (ii) rapid prototyping and computational benchmarking against human clinical data will enable fast and nonbiased validation of newly generated models. Copyright © 2017 Elsevier Ltd. All rights reserved.

Review of DoD Malaria Research Programs,

DTIC Science & Technology

1992-05-01

the irraliated sporozoite vaccine. Work in the mouse model system and then extrapolate to human malarias. Study naturally acquired immune ...recombinant vaccines. Work simultaneously in the mouse model system and with human malarias. 3. Identify targets and mechanisms of protective immunity not...multivalent vaccines that attack these same targets. 3. Working again in the mouse model, non- human primate model, andI human systems we

Animal models for prenatal gene therapy: rodent models for prenatal gene therapy.

PubMed

Roybal, Jessica L; Endo, Masayuki; Buckley, Suzanne M K; Herbert, Bronwen R; Waddington, Simon N; Flake, Alan W

2012-01-01

Fetal gene transfer has been studied in various animal models, including rabbits, guinea pigs, cats, dogs, and nonhuman primate; however, the most common model is the rodent, particularly the mouse. There are numerous advantages to mouse models, including a short gestation time of around 20 days, large litter size usually of more than six pups, ease of colony maintenance due to the small physical size, and the relatively low expense of doing so. Moreover, the mouse genome is well defined, there are many transgenic models particularly of human monogenetic disorders, and mouse-specific biological reagents are readily available. One criticism has been that it is difficult to perform procedures on the fetal mouse with suitable accuracy. Over the past decade, accumulation of technical expertise and development of technology such as high-frequency ultrasound have permitted accurate vector delivery to organs and tissues. Here, we describe our experiences of gene transfer to the fetal mouse with and without ultrasound guidance from mid to late gestation. Depending upon the vector type, the route of delivery and the age of the fetus, specific or widespread gene transfer can be achieved, making fetal mice excellent models for exploratory biodistribution studies.

Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome

DTIC Science & Technology

2016-08-01

AWARD NUMBER: W81XWH-15-1-0190 TITLE: Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome PRINCIPAL INVESTIGATOR: Dr. Paul...AND SUBTITLE 5a. CONTRACT NUMBER Neurosteroids Reverse Tonic Inhibition Deficits in Fragile X Syndrome 5b. GRANT NUMBER 5c. PROGRAM ELEMENT...Appendices……………………………………………………………11 2 1. Introduction Fragile X syndrome (FXS) is the most common form of inherited intellectual disability. In addition

Treatment of d-galactose induced mouse aging with Lycium barbarum polysaccharides and its mechanism study.

PubMed

Tang, Tao; He, Bixiu

2013-01-01

We evaluated the effects of Lycium barbarum polysaccharides LBP) on D-galactose aging model mouse, and explored its possible mechanism. Kunming mice were randomly divided into the control group, the model group, the high-dose LBP group, and the low-dose LBP group. Except the control group, D-galactose was used for modelling. The drug was administrated when modelling. Mouse behavioural, learning and memory changes were observed, and the contents of lipid peroxidation (LPO), lipofuscin (LF) and monoamine oxidase B (MAO-B) in mouse brain tissue and the weight of immune organs were measured after 6 weeks. Compared with the control group, mouse weight gain in the model group reduced significantly. Compared with model group, after mice drank LBP, the times of electric shock was less than aging mice (in which, the high-dose LBP group, P<0.05), and electric shock incubation period was longer (P<0.01). On Day 45 after modelling and drug administration, the contents of LPO, LF and MAO-B in mouse brain tissue in the model group increased significantly, while those in the drug administration groups decreased significantly. The thymus index in the aging model group decreased significantly; the thymus index and the spleen index in the high-dose LBP group and the low-dose LBP group rebounded significantly (P<0.01). We concluded that LBP has an anti-aging effect on D-galactose induced aging model mouse, and its mechanism may be related with the alleviation of glucose metabolism disorder and the resistance of the generation of lipid peroxide and other substances, which damage cell membrane lipid.

Mutagenicity testing with transgenic mice. Part II: Comparison with the mouse spot test

PubMed Central

Wahnschaffe, Ulrich; Bitsch, Annette; Kielhorn, Janet; Mangelsdorf, Inge

2005-01-01

The mouse spot test, an in vivo mutation assay, has been used to assess a number of chemicals. It is at present the only in vivo mammalian test system capable of detecting somatic gene mutations according to OECD guidelines (OECD guideline 484). It is however rather insensitive, animal consuming and expensive type of test. More recently several assays using transgenic animals have been developed. From data in the literature, the present study compares the results of in vivo testing of over twenty chemicals using the mouse spot test and compares them with results from the two transgenic mouse models with the best data base available, the lacI model (commercially available as the Big Blue® mouse), and the lacZ model (commercially available as the Muta™ Mouse). There was agreement in the results from the majority of substances. No differences were found in the predictability of the transgenic animal assays and the mouse spot test for carcinogenicity. However, from the limited data available, it seems that the transgenic mouse assay has several advantages over the mouse spot test and may be a suitable test system replacing the mouse spot test for detection of gene but not chromosome mutations in vivo. PMID:15676065

The Mouse Genome Database (MGD): facilitating mouse as a model for human biology and disease.

PubMed

Eppig, Janan T; Blake, Judith A; Bult, Carol J; Kadin, James A; Richardson, Joel E

2015-01-01

The Mouse Genome Database (MGD, http://www.informatics.jax.org) serves the international biomedical research community as the central resource for integrated genomic, genetic and biological data on the laboratory mouse. To facilitate use of mouse as a model in translational studies, MGD maintains a core of high-quality curated data and integrates experimentally and computationally generated data sets. MGD maintains a unified catalog of genes and genome features, including functional RNAs, QTL and phenotypic loci. MGD curates and provides functional and phenotype annotations for mouse genes using the Gene Ontology and Mammalian Phenotype Ontology. MGD integrates phenotype data and associates mouse genotypes to human diseases, providing critical mouse-human relationships and access to repositories holding mouse models. MGD is the authoritative source of nomenclature for genes, genome features, alleles and strains following guidelines of the International Committee on Standardized Genetic Nomenclature for Mice. A new addition to MGD, the Human-Mouse: Disease Connection, allows users to explore gene-phenotype-disease relationships between human and mouse. MGD has also updated search paradigms for phenotypic allele attributes, incorporated incidental mutation data, added a module for display and exploration of genes and microRNA interactions and adopted the JBrowse genome browser. MGD resources are freely available to the scientific community. © The Author(s) 2014. Published by Oxford University Press on behalf of Nucleic Acids Research.

Genetically engineered mouse models of craniopharyngioma: an opportunity for therapy development and understanding of tumor biology

PubMed Central

Martinez‐Barbera, Juan Pedro

2017-01-01

Abstract Adamantinomatous craniopharyngioma (ACP) is the commonest tumor of the sellar region in childhood. Two genetically engineered mouse models have been developed and are giving valuable insights into ACP biology. These models have identified novel pathways activated in tumors, revealed an important function of paracrine signalling and extended conventional theories about the role of organ‐specific stem cells in tumorigenesis. In this review, we summarize these mouse models, what has been learnt, their limitations and open questions for future research. We then discussed how these mouse models may be used to test novel therapeutics against potentially targetable pathways recently identified in human ACP. PMID:28414891

Mouse neuroblastoma cell based model and the effect of epileptic events on calcium oscillations and neural spikes

NASA Astrophysics Data System (ADS)

Kim, Suhwan; Baek, Juyeong; Jung, Unsang; Lee, Sangwon; Jung, Woonggyu; Kim, Jeehyun; Kang, Shinwon

2013-05-01

Recently, Mouse neuroblastoma cells are considered as an attractive model for the study of human neurological and prion diseases, and intensively used as a model system in different areas. Among those areas, differentiation of neuro2a (N2A) cells, receptor mediated ion current, and glutamate induced physiological response are actively investigated. The reason for the interest to mouse neuroblastoma N2A cells is that they have a fast growing rate than other cells in neural origin with a few another advantages. This study evaluated the calcium oscillations and neural spikes recording of mouse neuroblastoma N2A cells in an epileptic condition. Based on our observation of neural spikes in mouse N2A cell with our proposed imaging modality, we report that mouse neuroblastoma N2A cells can be an important model related to epileptic activity studies. It is concluded that the mouse neuroblastoma N2A cells produce the epileptic spikes in vitro in the same way as produced by the neurons or the astrocytes. This evidence advocates the increased and strong level of neurotransmitters release by enhancement in free calcium using the 4-aminopyridine which causes the mouse neuroblastoma N2A cells to produce the epileptic spikes and calcium oscillation.

Dynamics of circulating gamma delta T cell activity in an immunocompetent mouse model of high-grade glioma

USDA-ARS?s Scientific Manuscript database

Human gamma delta T cells are potent effectors against glioma cell lines in vitro and in human/mouse xenograft models of glioblastoma, however, this effect has not been investigated in an immunocompetent mouse model. In this report, we established GL261 intracranial gliomas in syngeneic WT C57BL/6 m...

Lack of species-specific difference in pulmonary function when using mouse versus human plasma in a mouse model of hemorrhagic shock.

PubMed

Peng, Zhanglong; Pati, Shibani; Fontaine, Magali J; Hall, Kelly; Herrera, Anthony V; Kozar, Rosemary A

2016-11-01

Clinical studies have demonstrated that the early and empiric use of plasma improves survival after hemorrhagic shock. We have demonstrated in rodent models of hemorrhagic shock that resuscitation with plasma is protective to the lungs compared with lactated Ringer's solution. As our long-term objective is to determine the molecular mechanisms that modulate plasma's protective effects in injured bleeding patients, we have used human plasma in a mouse model of hemorrhagic shock. The goal of the current experiments is to determine if there are significant adverse effects on lung injury when using human versus mouse plasma in an established murine model of hemorrhagic shock and laparotomy. Mice underwent laparotomy and 90 minutes of hemorrhagic shock to a mean arterial pressure (MAP) of 35 ± 5 mm Hg followed by resuscitation at 1× shed blood using either mouse fresh frozen plasma (FFP), human FFP, or human lyophilized plasma. Mean arterial pressure was recorded during shock and for the first 30 minutes of resuscitation. After 3 hours, animals were killed, and lungs collected for analysis. There was a significant increase in early MAP when mouse FFP was used to resuscitate animals compared with human FFP or human lyophilized plasma. However, despite these differences, analysis of the mouse lungs revealed no significant differences in pulmonary histopathology, lung permeability, or lung edema between all three plasma groups. Analysis of neutrophil infiltration in the lungs revealed that mouse FFP decreased neutrophil influx as measured by neutrophil staining; however, myeloperoxidase immunostaining revealed no significant differences in between groups. The study of human plasma in a mouse model of hemorrhagic shock is feasible but does reveal some differences compared with mouse plasma-based resuscitation in physiologic measures such as MAP postresuscitation. Measures of end organ function such as lung injury appear to be comparable in this acute model of hemorrhagic shock and resuscitation.

In vivo quantitative bioluminescence tomography using heterogeneous and homogeneous mouse models.

PubMed

Liu, Junting; Wang, Yabin; Qu, Xiaochao; Li, Xiangsi; Ma, Xiaopeng; Han, Runqiang; Hu, Zhenhua; Chen, Xueli; Sun, Dongdong; Zhang, Rongqing; Chen, Duofang; Chen, Dan; Chen, Xiaoyuan; Liang, Jimin; Cao, Feng; Tian, Jie

2010-06-07

Bioluminescence tomography (BLT) is a new optical molecular imaging modality, which can monitor both physiological and pathological processes by using bioluminescent light-emitting probes in small living animal. Especially, this technology possesses great potential in drug development, early detection, and therapy monitoring in preclinical settings. In the present study, we developed a dual modality BLT prototype system with Micro-computed tomography (MicroCT) registration approach, and improved the quantitative reconstruction algorithm based on adaptive hp finite element method (hp-FEM). Detailed comparisons of source reconstruction between the heterogeneous and homogeneous mouse models were performed. The models include mice with implanted luminescence source and tumor-bearing mice with firefly luciferase report gene. Our data suggest that the reconstruction based on heterogeneous mouse model is more accurate in localization and quantification than the homogeneous mouse model with appropriate optical parameters and that BLT allows super-early tumor detection in vivo based on tomographic reconstruction of heterogeneous mouse model signal.

Of Mice and Men: Comparative Analysis of Neuro-Inflammatory Mechanisms in Human and Mouse Using Cause-and-Effect Models.

PubMed

Kodamullil, Alpha Tom; Iyappan, Anandhi; Karki, Reagon; Madan, Sumit; Younesi, Erfan; Hofmann-Apitius, Martin

2017-01-01

Perturbance in inflammatory pathways have been identified as one of the major factors which leads to neurodegenerative diseases (NDD). Owing to the limited access of human brain tissues and the immense complexity of the brain, animal models, specifically mouse models, play a key role in advancing the NDD field. However, many of these mouse models fail to reproduce the clinical manifestations and end points of the disease. NDD drugs, which passed the efficacy test in mice, were repeatedly not successful in clinical trials. There are numerous studies which are supporting and opposing the applicability of mouse models in neuroinflammation and NDD. In this paper, we assessed to what extend a mouse can mimic the cellular and molecular interactions in humans at a mechanism level. Based on our mechanistic modeling approach, we investigate the failure of a neuroinflammation targeted drug in the late phases of clinical trials based on the comparative analyses between the two species.

NCI Mouse Repository | FNLCR Staging

Cancer.gov

The NCI Mouse Repository is an NCI-funded resource for mouse cancer models and associated strains. The repository makes strains available to all members of the scientific community (academic, non-profit, and commercial). NCI Mouse Repository strains

An extended Kalman filter for mouse tracking.

PubMed

Choi, Hongjun; Kim, Mingi; Lee, Onseok

2018-05-19

Animal tracking is an important tool for observing behavior, which is useful in various research areas. Animal specimens can be tracked using dynamic models and observation models that require several types of data. Tracking mouse has several barriers due to the physical characteristics of the mouse, their unpredictable movement, and cluttered environments. Therefore, we propose a reliable method that uses a detection stage and a tracking stage to successfully track mouse. The detection stage detects the surface area of the mouse skin, and the tracking stage implements an extended Kalman filter to estimate the state variables of a nonlinear model. The changes in the overall shape of the mouse are tracked using an oval-shaped tracking model to estimate the parameters for the ellipse. An experiment is conducted to demonstrate the performance of the proposed tracking algorithm using six video images showing various types of movement, and the ground truth values for synthetic images are compared to the values generated by the tracking algorithm. A conventional manual tracking method is also applied to compare across eight experimenters. Furthermore, the effectiveness of the proposed tracking method is also demonstrated by applying the tracking algorithm with actual images of mouse. Graphical abstract.

Mouse Models for Down Syndrome-Associated Developmental Cognitive Disabilities

PubMed Central

Liu, Chunhong; Belichenko, Pavel V.; Zhang, Li; Fu, Dawei; Kleschevnikov, Alexander M.; Baldini, Antonio; Antonarakis, Stylianos E.; Mobley, William C.; Yu, Y. Eugene

2011-01-01

Down syndrome (DS) is mainly caused by the presence of an extra copy of human chromosome 21 (Hsa21) and is a leading genetic cause for developmental cognitive disabilities in humans. The mouse is a premier model organism for DS because the regions on Hsa21 are syntenically conserved with three regions in the mouse genome, which are located on mouse chromosome 10 (Mmu10), Mmu16 and Mmu17. With the advance of chromosomal manipulation technologies, new mouse mutants have been generated to mimic DS at both the genotypic and phenotypic levels. Further mouse-based molecular genetic studies in the future may lead to the unraveling of the mechanisms underlying DS-associated developmental cognitive disabilities, which would lay the groundwork for developing effective treatments for this phenotypic manifestation. In this review, we will discuss recent progress and future challenges in modeling DS-associated developmental cognitive disability in mice with an emphasis on hippocampus-related phenotypes. PMID:21865664

Estimating individual contribution from group-based structural correlation networks.

PubMed

Saggar, Manish; Hosseini, S M Hadi; Bruno, Jennifer L; Quintin, Eve-Marie; Raman, Mira M; Kesler, Shelli R; Reiss, Allan L

2015-10-15

Coordinated variations in brain morphology (e.g., cortical thickness) across individuals have been widely used to infer large-scale population brain networks. These structural correlation networks (SCNs) have been shown to reflect synchronized maturational changes in connected brain regions. Further, evidence suggests that SCNs, to some extent, reflect both anatomical and functional connectivity and hence provide a complementary measure of brain connectivity in addition to diffusion weighted networks and resting-state functional networks. Although widely used to study between-group differences in network properties, SCNs are inferred only at the group-level using brain morphology data from a set of participants, thereby not providing any knowledge regarding how the observed differences in SCNs are associated with individual behavioral, cognitive and disorder states. In the present study, we introduce two novel distance-based approaches to extract information regarding individual differences from the group-level SCNs. We applied the proposed approaches to a moderately large dataset (n=100) consisting of individuals with fragile X syndrome (FXS; n=50) and age-matched typically developing individuals (TD; n=50). We tested the stability of proposed approaches using permutation analysis. Lastly, to test the efficacy of our method, individual contributions extracted from the group-level SCNs were examined for associations with intelligence scores and genetic data. The extracted individual contributions were stable and were significantly related to both genetic and intelligence estimates, in both typically developing individuals and participants with FXS. We anticipate that the approaches developed in this work could be used as a putative biomarker for altered connectivity in individuals with neurodevelopmental disorders. Copyright © 2015 Elsevier Inc. All rights reserved.