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Fragile X and autism: Intertwined at the molecular level leading to targeted treatments

Randi Hagerman, Gry Hoem, Paul Hagerman

Molecular Autism · 2010 · Review

doi:10.1186/2040-2392-1-12

Abstract

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.

Full text

From PubMed Central, U.S. National Library of Medicine, as current on Oct 20, 2026. Paragraph numbers are ours, so an answer can point at one.

Introduction

1Fragile X syndrome (FXS) is an important subtype of autism, both because of its frequency and because knowledge of the molecular mechanisms involved in its pathogenesis has facilitated the development of targeted treatments with the potential to reverse or dramatically improve both behavioral and cognitive deficits. Because FXS is the most common single gene cause of autism, responsible for 2% to 6% of all cases of autism, it is clinically recommended that all individuals diagnosed with autism or ASD should have the FX DNA test (both PCR and Southern blot) when the etiology of their autism is not known. FXS is nearly always caused by a trinucleotide (CGG) repeat expansion, located in the 5' untranslated region of the FMR1 gene, to a length of greater than 200 repeats (full mutation range). Full mutation expansions typically lead to methylation of the gene, reduced or absent transcription, and consequent decreased reduction in translation of the FMR1 protein (FMRP), the proximal basis of FXS. FMRP levels are correlated with the degree of clinical involvement including physical, cognitive and structural/functional brain involvement.

2Approximately 30% of males with FXS have full autism, as determined by the standardized criteria of the Autism Diagnostic Observation Scale (ADOS) and the Autism Diagnostic Interview (ADI-R). An additional 30% of boys have pervasive developmental disorder, not otherwise specified (PDD-NOS). Among the remaining patients with FXS, of those who do not meet the criteria for an autism spectrum disorder (ASD) diagnosis, the majority have one or more autistic features, such as hand flapping, poor eye contact and tactile defensiveness.

3A premutation CGG-repeat range (55 to 200 repeats) was initially defined in terms of an increased frequency of expansion of the CGG repeat to the full mutation range when transmitted by a premutation (carrier) woman. All children with the full mutation have a carrier mother, although a female patient with a premutation could have received this mutation from either her mother or her father. Moreover, the propensity for transmission of a full mutation allele increases with increasing CGG repeat number in the mother. A father who is a carrier of either a premutation or full mutation allele will pass only a premutation to all of his daughters, presumably due to selective production of premutation allele-bearing sperm.

4Carriers of premutation alleles were generally considered to be clinically uninvolved until premature ovarian failure, recently renamed FX-associated primary ovarian insufficiency (FXPOI), was reported. Subsequently, the late onset neurodegenerative disorder, FX-associated tremor ataxia syndrome (FXTAS), was described, further establishing clinical involvement among premutation carriers. It is now evident that a spectrum of neurodevelopmental and aging/neurological problems are associated with premutations, including autism and ASD. Most individuals with a premutation are neither developmentally disabled nor do they have autism; however, a subgroup does experience cognitive, emotional and/or behavioral involvement. There is a negative correlation between CGG repeat number and the level of FMRP in a premutation range, which predisposes individuals in the high end of a premutation range to cognitive and behavioral impairment. In addition, all individuals with a premutation have elevated FMR1 mRNA, whereas the opposite occurs in the full mutation. Thus, the cognitive and behavioral impairments in a premutation and full mutation ranges are likely to have both distinct and overlapping mechanisms.

Clinical and molecular involvement in FXS, and association with autism

5The basis for incomplete penetrance of autism (30%) or PDD-NOS (30%) among individuals with FXS is not known. However, there is evidence that patients with additional medical disorders that affect the CNS, such as seizures or additional genetic problems, have an increased risk for autism compared with patients with FXS alone. For those with both FXS and autism, there is a spectrum of involvement with significant heterogeneity, both cognitively and behaviorally, with IQ values ranging from severely intellectually impaired to normal, particularly in females. However, there is a strong association between low IQ and the autism diagnosis in both males and females with FXS. The cause of this heterogeneity is related to background genetic effects and environmental effects that influence IQ, social abilities, anxiety, attention deficit hyperactive disorder and additional features that are components of the FXS phenotype (Figure 1). Background genetic effects include additional pathological mutations (FXS has been reported with sex chromosome disorders, Down syndrome, Tourette syndrome and other conditions, allelic variants, and gene expression changes). An example of the later condition is the Prader-Willi phenotype (PWP) of FXS, in which there is no structural or methylation change at 15q 11-13; rather, there is significant downregulation of expression of CYFIP 1, which is located at the 15q locus in Prader-Willi syndrome (PWS). Males with the PWP of FXS have severe obesity, hyperphagia and hypogenitalia, and a higher rate of ASD than those with FXS without the PWP.

6Environmental influences on the phenotype of FXS include exposures to toxins (for example, alcohol, leading to fetal alcohol syndrome and FXS), abuse (physical or sexual), neglect, perinatal asphyxia, head trauma, seizures and socioeconomic status. Additional environmental exposures leading to further toxicity are just beginning to be explored in both premutation and full mutation involvement, as they are in idiopathic autism. Such studies are occurring at a cellular level in premutation neurons; these neurons die earlier than do control neurons, with increased cell death documented by 21 days in culture. In addition, mitochondrial dysfunction has been documented in fibroblasts and brain tissue in premutation carriers both with and without FXTAS. We hypothesize that premutation neurons are more vulnerable to environmental toxins, and clinical case reports appear to support this notion.

7The absence of FMRP in individuals with FXS has significant consequences in the translation of dozens and probably hundreds of proteins. Because FMRP usually suppresses translation, its absence leads to broad translational upregulation in the hippocampus. Recent studies by Darnell et al. and others have demonstrated linkage between FMRP and many proteins that are related to autism, including neuroligin 3 and 4, neurorexin, PDP (postsynaptic density protein) 95, CYFIP (cytoplasmic FMR1 interacting protein) 1 and 2, SHANK (Src homology 3 and multiple ankyrin repeat domains)3, Arc, PTEN (phosphatase and tensin homolog), MAPK (mitogen activated protein kinase), JAKMIP (janus kinase and microtubule interacting protein)1 and HERC (homologous to the E6-AP carboxyl terminus) and regulator of chromosome condensation (RCC)1-like domain-containing protein) 2, among others. Most of these proteins are associated with synapse formation and plasticity; however, the PTEN gene encodes a dual specificity phosphatase effecting G1 cell cycle arrest and/or apoptosis, and 17% (3/18) of individuals with autism and macrocephaly were found to have a PTEN mutation. Macrocephaly also occurs in FXS, often with a broad forehead remarkably similar to the broad foreheads described by Butler and colleagues; this characteristic is hypothesized to be related to the downregulation of PTEN that occurs in FXS. Expression of JAKMIP1 and the G protein coupled receptor (GRP)155 were both altered by reduction of FMRP (seen in FXS) or induction of CYFIP1 (seen in the 15q duplication form of autism) in vitro. These proteins were also dysregulated in boys with idiopathic ASD relative to their unaffected siblings. Both CYFIP1 (a partner protein to FMRP and regulated by FMRP) and JAKMIP1 are involved with the RacGTPase system, which modulates the neurite development that is crucial for proper brain connectivity. There is also evidence for upregulation of the mammalian target of rapamycin (mTOR) pathway in the hippocampus of the knockout (KO)mouse and in studies of humans with FXS. The mTOR pathway is dysregulated in several other genetic disorders that are associated with autism, such as tuberous sclerosis (TS). These findings have stimulated targeted treatments using rapamycin to downregulate the mTOR system in patients with TS, with initially positive results. The overlap of molecular mechanisms in those with a premutation or the full mutation and idiopathic autism is shown in Figure 2.

8Recently, a number of studies have directly compared patients with FXS and those with autism without FXS. There are unique structural differences in the central nervous system (CNS) between the two disorders even when both disorders have comparable degrees of autism as assessed by standardized behavioral measures. Those with FXS have an enlarged caudate compared with typically developing individuals and those with autism, whereas those with autism have a larger amygdala compared with FXS or controls. These differences continue to evolve with age, as does the severity of the autistic features in FXS. Therefore, from early in life, and probably in utero, there are structural CNS changes that are related to the lack of FMRP. The dysregulation of proteins that are important for synaptic plasticity and connectivity in the brain leads to the gradual deficits in socialization, behavior and cognition that characterize the FXS phenotype. Although eye contact problems are usually not present during the first year of life, they evolve over time, as do the sensory hyperarousal, anxiety, motor and social deficits. Hoeft et al. have reported that the early trajectory of brain growth abnormalities in FXS becomes more exaggerated over time and includes enhanced growth of the caudate, nucleus basalis and thalamus, compared with controls. Those authors also documented enhanced white matter volume, particularly of the striatal-frontal regions, becoming more dramatic in the early years (1 to 3 years of age), which suggests axonal pathology as opposed to secondary connectional dysregulation. Their work further suggests that the earlier the intervention is begun, the better the outcome for an individual with FXS. These findings provide neurobiological support for initiating interventions as early in the lifespan as possible, although further clinical studies are needed. A summary of treatment for FXS was reviewed by Hagerman et al..

RNA toxicity and a premutation carrier

9The discovery of the neurodegenerative disorder, FXTAS, in older adult carriers of premutation alleles, coupled with increased FMR1 transcriptional activity in the premutation range, led to the recognition of an entirely distinct pathogenic mechanism associated with the FMR1 gene: RNA toxicity. A range of studies on the adverse consequences of expressing the expanded CGG repeat in human, animal and cell models has helped to establish an RNA toxicity model involving a toxic gain of function of premutation FMR1 RNA. However, although carriers of premutation alleles have elevated FMR1 mRNA, the strongest argument for an RNA-based toxicity mechanism in both FXTAS and FXPOI, is that these clinical syndromes are limited to a premutation repeat range, where the gene is active; that is, low levels (or absence) of FMRP do not cause either FXTAS or FXPOI. However, moderately lowered FMRP levels in the upper premutation range may compound the effects of elevated RNA levels (a mechanistic issue that still needs to be resolved) but the primary effect appears to be expression of the expanded CGG-repeat RNA. A supporting argument for an RNA-based mechanism is that the FMR1 mRNA is found within the characteristic intranuclear neuronal and astrocytic inclusions of FXTAS.

10FXTAS was originally described as a late adult-onset neurodegenerative disorder; however, there is an emerging view that FXTAS, and probably also FXPOI, is the end stage of a process that actually begins in early development, and that may be responsible for the emotional and behavioral problems, cognitive impairment, ASD and seizure activity experienced by children who are carriers of premutation alleles. This view is based on a combination of animal and cell-based studies for early abnormalities resulting from expression of a premutation allele. In particular, Chen et al. demonstrated that in cultured hippocampal neurons from day 1 postnatal premutation (knock-in; KI) mice, there were CGG repeat-dependent decreases in both the number of branches and the interbranch lengths, and decreased longevity in culture. Moreover, Garcia-Arocena et al. observed abnormal lamin A/C architecture, with loss of ring-like nuclear staining, in embryonic fibroblasts from the KI mouse. In behavioral studies with the KI mice, there were progressive deficits in spatial processing (but no motor involvement) in mice as young as 12 weeks. These observations, plus elevated levels of FMR1 mRNA in children with premutation alleles, support the presence of an early developmental component of FMR1 mRNA-associated toxicity.

11Based on the toxic RNA gain of function model for myotonic dystrophy, in which disease pathogenesis involves the sequestration of one or more proteins by an expanded rCUG repeat in the 3' untranslated region of the myotonic dystrophy protein kinase (DMPK) gene, the first view of FXTAS envisioned a similar, direct-RNA mechanism in which proteins would be sequestered by the expanded CGG repeat. A growing number of animal and cell- l-based studies support this 'direct RNA' model. Recently, Sellier et al.presented evidence for both sequestration of an RNA processing protein, Sam68 and the consequent altered splice-site regulation of several RNAs whose splicing is known to be regulated by Sam68. In addition to their demonstration of the functional consequences of Sam68 sequestration, Sellier et al. demonstrated that the incorporation of the protein into nuclear aggregates displayed a CGG-repeat cutoff that meant aggregation only occurred for expansions exceeding ~40 CGG repeats. More recently, Sellier et al. also reported that a consequence of this sequestration is dysregulation of microRNAs, which may be related to the clinical problems of premutation carriers.

12It should be noted that although the sequestration model remains the most viable mechanism for RNA toxicity, the clinical data only support the requirement for transcription. Thus, a role for other mechanisms such as RNA-triggered signaling or co-transcriptional mechanisms cannot be discounted (Figure 3). Evidence for a direct RNA-based (for example, sequestration) model cannot exclude the possibility that co-transcriptional RNA, or even DNA, has a role in the pathogenesis. Entezam and Usdin observed that the DNA-repair protein ATR is recruited to CGG expansions, and the fact that another DNA-repair protein, γ-H2AX, is found in the intranuclear FXTAS inclusions, suggests that transcription-induced DNA damage could also trigger the pathogenesis of premutation-associated disorders.

13Recent work from the laboratory of Guilivi has demonstrated mitochondrial dysfunction in fibroblasts and brain samples in premutation carriers both with and without FXTAS. Mitochondrial dysfunction in carriers included uncoupling between electron transport and synthesis of ATP in addition to decreased levels of mitochondrial proteins including the ATPase β-subunit (ATPB) from complex V, the cytochrome c oxidase subunit from complex IV (CCOIV) and manganese superoxide dismutase as part of the mitochondrial antioxidant defense. The levels of the mitochondrial proteins correlated inversely with the CGG repeat numbers in the premutation range. These protein changes increased oxidative stress and oxidatively modified mitochondrial proteins, and activated the unfolded protein response and phosphorylation of the alpha subunit of the heterotrimeric eukaryotic translational initiation factor 2 (eIF2α), resulting in a decrease in protein translation. Similar types of mitochondrial abnormalities have been seen in those with autism without a FX mutation (Giulivi et al. unpublished data). Specifically, Olivera et al. reported that 14 of 69 patients with autism had hyperlactacidemia, and in 5 of 11 of these patients who underwent a deltoid muscle biopsy, there was a mitochondrial respiratory chain disorder with enzyme function that was <20% of normal mean activity, including complex I, complex IV and complex V abnormalities. Weissman et al. studied 25 patients with autism and evidence of oxidative phosphorylation abnormalities, and found 19 with elevated lactate levels, 64% with complex I deficiency and 20% with complex III deficiency. Two of the patients had pathological mitochondrial DNA mutations. Other reports of mitochondrial gene mutations in children with autism have also been reported.

Clinical involvement of some premutation carriers

14Although autism and other clinical involvement in a subgroup of young premutation carriers was initially thought to be only an occasional occurrence, research cohorts demonstrated that approximately 14% of boys and 5% of girls with a premutation had ASD. More recent studies demonstrated a high rate of ASD (73%) in boys with a premutation who were referred clinically to the UC Davis MIND Institute, although this was much lower in premutation males who were identified by cascade testing (7%) compared with their brothers who did not have a premutation (0%). Although there is clearly a bias towards an ASD phenotype in those who present clinically, a recent online family questionnaire completed by over 1200 families affected by FXS found that 19% of 57 males with a premutation had a diagnosis of autism, which was significantly higher than control boys (5%). In this survey 1% of 199 females with a premutation also had a diagnosis of autism. This same survey found that 33% of boys with a premutation had developmental delays, which was significantly higher than in a group of age-matched boys without a premutation (1.8%). A completely unbiased population of premutation carriers that should be followed carefully are those diagnosed by screening as newborns; three studies are currently in progress in the USA.

15Studies of neuropsychological deficits in premutation carriers during adulthood have been complicated because of the subclinical CNS changes that can occur related to the development of FXTAS. Studies have detected deficits in executive function in a subgroup of males with a premutation, but not in the corresponding group of females. In contrast to these four reports, Hunter et al. found no neuropsychological deficits in 54 men with a premutation who were aged under 50 years, although the Behavioral Dyscontrol Scale (BDS), which was found to be most sensitive to executive dysfunction in older male carriers, was not used. Clearly, recruitment bias is likely to affect adult premutation studies in neuropsychological testing and in emotional assessments. In contrast to the neuropsychological testing, standardized emotional assessments have demonstrated problems with anxiety and/or depression in both males and females with a premutation, both with and without FXTAS, compared with controls at multiple centers

16An emerging phenotype includes the finding of autoimmune problems in a subgroup of women with a premutation. These problems include fibromyalgia, hypothyroidism and multiple sclerosis, and they can occur in women with a premutation both with and without FXTAS. Hunter et al. found that women with irregular cycles reported higher rates of thyroid disease in addition to depression/anxiety. The molecular process leading to the autoimmune problems are unknown, although they are most likely related to the RNA toxicity. Predisposing factors leading to autoimmune disease in some females are likely to be genetic, because in our clinical experience, they cluster in families. Because of concern about the genetic factors that underlie both autoimmune disease and autism, we studied whether there is an increase in ASD with FXS in the children of female carriers who have autoimmune disease, compared with carriers who do not have autoimmune disease. The odds ratio (OR) for ASD was 1.27 (P = 0.51) which was not significant; however, the ORs for seizures and tics in the offspring were 3.81 (P = 0.031) and 2.94 (P = 0.019) respectively. These results raise the possibility that there are intergenerational autoimmune factors or perhaps auto-antibodies that affect the prevalence of seizures and tics in the offspring of mothers with a premutation and autoimmune disease.

FMRP function throughout life leading to targeted treatments for FXS

17FMRP is an mRNA-binding protein that is important for mRNA transport, mRNA stabilization and translation of mRNA into protein at the synapse. FMRP is also a factor in the regulation of adult neurogenesis, so in the absence of FMRP there is dysregulation of glycogen synthase kinase (GSK)3β, reduced β-catenin and defective Wnt signaling. These alterations lead to downregulation of neurogenin 1, which is an early initiator of neuronal differentiation and an inhibitor of astrocyte differentiation. Therefore, FMRP is important throughout life and there is a high incidence of motor problems, including Parkinson disease (PD), with aging in those with FXS. In addition, in neuropathologic studies, there is evidence of migration problems in the hippocampus and in the cerebellum in those with FXS (Greco et al,. unpublished data), which are similar to those reported in individuals with autism. These problems may be related to dysregulation of Wnt signaling in both FXS and autism.

18Perhaps the most important change in protein expression in the absence of FMRP is the excess basal translation of proteins involved in the metabotropic glutamate receptor (mGluR) 5 receptor pathway. Bear and colleagues have proposed the mGluR theory of FX, suggesting that the deficits associated with FXS are related to upregulation of the downstream effectors of the mGluR5 pathway, leading to enhanced long-term depression (LTD), and that treatment with an mGluR5 antagonist could be a targeted treatment for FXS. Both FMRP and mGluRs play important roles in synaptogenesis and synaptic plasticity, and in the absence of FMRP there are long, thin and immature dendritic spines in both human and animal models of FXS. There are also enhanced, abnormal epileptiform discharges consistent with an enhanced rate of clinical seizures in FXS.

19Support for the 'mGluR theory' has been shown by generating FMR1 mutant mice with a 50% reduction in mGluR5 expression. The mGluR5 deficiency rescued most of the KO mouse abnormalities including altered ocular dominance plasticity, increased density of dendritic spines on cortical pyramidal neurons, increased basal protein synthesis in the hippocampus, exaggerated inhibitory avoidance extinction, audiogenic seizures and accelerated body growth. However, macroorchidism was not rescued. This work is supportive of the proposal by Bear et al.that excessive mGluR5 signaling is responsible for the psychiatric and neurological symptoms of FXS, including cognitive deficits, seizures, anxiety, perseverative movements and social deficits.

20Use of mGluR5 antagonists in animal models of FXS further supports the mGluR theory. MPEP (2-methyl-6-phenylethynyl pyridine hydrochloride) is a potent, highly selective antagonist of mGluR5 receptors. In vitro, both MPEP and fenobam, another mGluR5 antagonist, were able to rescue hippocampal dendritic abnormalities in the KO mice. MPEP has reversed audiogenic seizures, epileptiform discharges, open field hyperactivity and the defect in prepulse inhibition (PPI) of the startle response in KO mice. When MPEP and lithium, a partial mGluR5 antagonist that also blocks GSK3β, were given to dfmr1 loss of function Drosophila mutants, the flies had restored normal courtship behavior, memory and brain structural abnormalities through the reduction of mGluR activity. MPEP is toxic to humans, so other mGluR5 antagonists including fenobam have been studied in FXS. Fenobam was found to be safe in a single dose trial in 12 adults with FXS. There were improvements in hyperactivity and anxiety, and 50% showed at least a 20% improvement in PPI. Currently there are two additional mGluR5 antagonists undergoing trials in adults with FXS at multiple centers.

21Other mechanisms to downregulate glutamate release and modulate mGluR overactivity have been investigated. γ Aminobutyric acid (GABA)B receptor agonists, such as baclofen, inhibit both presynaptic release of glutamate and postsynaptic transmission and/or intracellular signaling downstream from mGluR5. Baclofen has been shown to be efficacious in treating hyperactivity, marble burying (Seaside Therapeutics, unpublished data) and audiogenic seizure phenotypes in FX KO mice. A double-blind, placebo-controlled, crossover trial of arbaclofen, the right sided isomer of baclofen that is significantly more potent than regular baclofen as a GABA agent, has just been completed at multiple centers,and involved over 60 individuals with FXS (aged 6 years and older). The preliminary safety and efficacy results are positive, with improvement in the Clinical Global Impression Improvement scale in those with the most severe baseline ratings. There are also preliminary studies that are taking place involving individuals with autism without FXS, and these studies have also produced preliminary positive results. Therefore, further studies on both FXS and autism are set to take place.

22The GABAergic system is also dysregulated in FXS, and GABA agents are important to consider for targeted treatment studies in FXS. GABA is a major inhibitory neurotransmitter receptor in the brain, which is important in anxiety, depression, epilepsy, insomnia, and learning and memory. GABA-mediated inhibition is important for terminating ictal discharges and the spread of hyperexcitability, which can lead to seizures.

23There are two main subtypes of GABA receptors: GABAA and GABAB. The main difference between them is that the first is a ligand gated Cl- channel that gives fast inhibition, whereas the latter is a G-protein coupled receptor which gives slower and more prolonged inhibitory signals. The metabotropic GABAB receptor can either be presynaptic and inhibit the release of neurotransmitters through downregulation of high-voltage activated Ca2+-channels; or, when postsynaptic, decrease neuronal excitability through its influence on K+ channels. Thus, GABAB agonists such as arbaclofen mediate their downregulating effects on either side of the synapse. The ionotropic GABAA receptor is usually localized postsynaptically, and their activation leads to opening of Cl- channels and hyperpolarization of the membrane potential, thus making it difficult for excitatory neurotransmitters such as glutamate to generate an action potential. GABAA receptors are more abundant than GABAB receptors in mammalian brain, and disorders such as epilepsy, sleep disorders and anxiety are now being treated using drugs that act on the GABAA receptor.

24Direct binding between FMRP and the mRNA of the delta subunit of the GABAA receptor has been shown. Reduced expression and dysfunction of several subunits of the GABAA receptor (α1, α3, α4; β1, β2; γ1, γ2 and δ) have been shown in FX animal models. FMR1 Drosophila mutants destined to die from glutamate toxicity were rescued after administering molecules involved in the GABAergic pathway. In addition, abnormal male courtship behavior and mushroom body abnormalities were rescued by GABA agents.

25There is a profound reorganization of neocortical inhibitory circuits of GABAergic intraneurons in the KO mouse. Recent evidence indicates that deficits in GABA-mediated inhibition may underlie many of the key symptoms in FXS, including the seizures, anxiety and autistic-like behaviors. The neocortex in KO mice exhibits a marked reduction in the density of GABAergic interneurons that stain with parvalbumin. Moreover, electrophysiological studies in brain slices from these animals exhibit impaired GABAA receptor-mediated inhibitory function. In addition to a gross reduction in GABA-mediated inhibition caused by the maldevelopment of inhibitory circuits and the loss of GABAergic interneurons, there is also evidence of altered GABAA receptor subunit expression in the FX KO mouse. In particular, there appears to be a selective reduction in the expression of δ subunits. Global expression analysis by means of the differential display in the FX mouse model revealed consistent underexpression of only three genes, one of which was the GABAA receptor subunit δ. As GABAA receptors are the major inhibitory receptors in the brain, and are specifically involved in processes that are disturbed in FX, including neuronal excitability (leading to enhanced seizure susceptibility), anxiety, sleep and learning, enhancement of the function of GABAA receptors may have major therapeutic benefits for FXS. Kooy and colleagues have demonstrated that use of the GABAA agonist ganaxolone (3α-hydroxy-3β-methyl-5α-pregnan-20-one) improved seizures in the KO mouse model of FXS. Ganaxolone is a 3β-methylated synthetic analog of the progesterone metabolite allopregnanolone, which is itself a neuroactive steroid. Unlike progesterone, neither allopregnanolone nor ganaxolone have direct hormonal activity via progesterone receptor activation, and cannot cause hormonal side-effects. However, allopregnanolone and ganaxolone are powerful positive allosteric modulators of GABAA receptors. Human trials indicate that ganaxolone is well tolerated and that it may be efficacious in the treatment of diverse forms of epilepsy in children and adults. Plans for studies on ganaxolone are currently underway in children and adults with FXS.

26Minocycline, a widely used antibiotic used to treat acne and skin infections, is another promising drug that may target core symptoms of FXS and autism. Minocycline inhibits matrix metalloproteinase (MMP)-9 and reduces inflammation in the central nervous system. MMPs are enzymes involved in synaptic plasticity, and are associated with immature dendritic spine morphology; MMP-9 is elevated in FXS. When minocycline was administered to FMR1 KO mice, their hippocampal neurons exhibited mature dendritic spines, and behaviorally, they showed decreased anxiety and improved exploration skills. Off-label use of minocycline to treat 50 individuals with FXS resulted in two-thirds of families noticing positive improvements in their child's language, attention and/or behavioral improvements while on the medication. An open-label trial is ongoing to investigate the effects of minocycline on children with regressive autism at the National Institute of Mental Health (NIMH). Paribello reported beneficial effects on the CGI and the Aberrant Behavior checklist in an open trial of minocycline involving patients with FXS who were aged 13 and older. Currently, a double-blind, placebo-controlled clinical trial is in progress at the Medical Investigation of Neurodevelopmental Disorders (MIND) Institute for individuals with FXS who are aged 3.5 to 16 years

27FXS has led the way for targeted treatments in neurodevelopmental disorders, and many of the treatments guided by molecular abnormalities in FXS may also be helpful for non-FX autism. The treatment trials will now combine targeted treatments, which strengthen synaptic connections, with enhanced educational and behavioral interventions to further develop appropriate synaptic connections in FXS. These targeted treatments combined with educational interventions look promising for reversing the intellectual and behavioral problems of FXS. Because of the shared neurobiological and molecular pathways, these interventions will hopefully also prove helpful in a subset of patients with idiopathic autism

Conclusions

28FX syndrome and autism are intertwined, because FMRP regulates the translation of many messages that affect synaptic plasticity and connectivity in the central nervous system. The absence of FMRP also leads to upregulation of mGluR5 pathways and downregulation of GABAA pathways. Targeted treatments to reverse these problems are currently being studied in patients with FXS. Many of these targeted treatments may also be helpful for ASD without FXS.

29A premutation can also cause ASD, particularly in a subset of young males, and the mechanism of involvement relates to elevated mRNA levels causing dysregulation of numerous proteins, early neuronal cell death in culture, mitochondrial dysfunction and vulnerability to environmental toxicity. Targeted treatments are currently being developed for premutation involvement in early childhood, and also for neurodegenerative problems including FXTAS in aging individuals.

Competing interests

30RH has received funding from Seaside Therapeutics, Novartis, Roche, Forest, Johnson & Johnson and Curemark for clinical trials, and also consults with Novartis and Roche regarding clinical trials in fragile X syndrome. PH is an unpaid consultant with Asuragen, and has a filed patent application for an FMR1 genotyping method. GH has no conflicts of interest.

Authors' contributions

31All authors helped draft the manuscript, and all authors read and approved the final manuscript.

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Rogers SJ Wehner EA Hagerman RJ The behavioral phenotype in fragile X: Symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disordersJ Dev Behav Pediatr2001 22409417
Not in our library10.1097/00004703-200112000-00008
13.
Kaufmann WE Cortell R Kau AS Bukelis I Tierney E Gray RM Cox C Capone GT Stanard P Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviorsAm J Med Genet2004 129A225234
Not in our library10.1002/ajmg.a.30229
14.
Hatton DD Sideris J Skinner M Mankowski J Bailey DB Jr Roberts JE Mirrett P Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRPAm J Med Genet A2006 14018041813
Not in our library10.1002/ajmg.a.31286
15.
Hall SS Lightbody AA Reiss AL Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndromeAm J Ment Retard2008 1134453
Not in our library10.1352/0895-8017(2008)113[44:csaabi]2.0.co;2
16.
McConkie-Rosell A Abrams L Finucane B Cronister A Gane LW Coffey SM Sherman S Nelson LM Berry-Kravis E Hessl D Chiu S Street N Vatave A Hagerman RJ Recommendations from multi-disciplinary focus groups on cascade testing and genetic counseling for fragile X-associated disordersJ Genet Couns2007 16593606
Not in our library10.1007/s10897-007-9099-y
17.
Reyniers E Vits L De Boulle K Van Roy B Van Velzen D de Graaff E Verkerk AJ Jorens HZ Darby JK Oostra B The full mutation in the FMR-1 gene of male fragile X patients is absent in their spermNat Genet1993 4143146
Not in our library10.1038/ng0693-143
18.
Cronister A Schreiner R Wittenberger M Amiri K Harris K Hagerman RJ Heterozygous fragile X female: historical, physical, cognitive, and cytogenetic featuresAm J Med Genet1991 38269274
Not in our library10.1002/ajmg.1320380221
19.
Hagerman RJ Leehey M Heinrichs W Tassone F Wilson R Hills J Grigsby J Gage B Hagerman PJ Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile XNeurology2001 57127130
Not in our library10.1212/wnl.57.1.127
20.
Jacquemont S Hagerman RJ Leehey M Grigsby J Zhang L Brunberg JA Greco C Des Portes V Jardini T Levine R Berry-Kravis E Brown WT Schaeffer S Kissel J Tassone F Hagerman PJ Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlatesAm J Hum Genet2003 72869878
Not in our library10.1086/374321
21.
Aziz M Stathopulu E Callias M Taylor C Turk J Oostra B Willemsen R Patton M Clinical features of boys with fragile X premutations and intermediate allelesAm J Med Genet B Neuropsychiatr Genet2003 121119127
Not in our library10.1002/ajmg.b.20030
22.
Bourgeois JA Coffey SM Rivera SM Hessl D Gane LW Tassone F Greco C Finucane B Nelson L Berry-Kravis E Grigsby J Hagerman PJ Hagerman RJ A review of fragile X premutation disorders: expanding the psychiatric perspectiveJ Clin Psychiatry2009 70852862
Not in our library10.4088/jcp.08r04476
23.
Chonchaiya W Schneider A Hagerman RJ Fragile X: a family of disordersAdv Pediatr2009 56165186
Not in our library10.1016/j.yapd.2009.08.008
24.
Coffey SM Cook K Tartaglia N Tassone F Nguyen DV Pan R Bronsky HE Yuhas J Borodyanskaya M Grigsby J Doerflinger M Hagerman PJ Hagerman RJ Expanded clinical phenotype of women with the FMR1 premutationAm J Med Genet A2008 146A10091016
Not in our library10.1002/ajmg.a.32060
25.
Farzin F Perry H Hessl D Loesch D Cohen J Bacalman S Gane L Tassone F Hagerman P Hagerman R Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutationJ Dev Behav Pediatr2006 27S137S144
Not in our library10.1097/00004703-200604002-00012
26.
Goodlin-Jones B Tassone F Gane LW Hagerman RJ Autistic spectrum disorder and the fragile X premutationJ Dev Behav Pediatr2004 25392398
Not in our library10.1097/00004703-200412000-00002
27.
Tassone F Hagerman RJ Taylor AK Gane LW Godfrey TE Hagerman PJ Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndromeAm J Hum Genet2000 66615
Not in our library10.1086/302720
28.
Garcia-Nonell C Ratera ER Harris S Hessl D Ono MY Tartaglia N Marvin E Tassone F Hagerman RJ Secondary medical diagnosis in fragile X syndrome with and without autism spectrum disorderAm J Med Genet A2008 146A19111916
Not in our library10.1002/ajmg.a.32290
29.
Stevens L Tartaglia N Hagerman R Riley K Clinical report: a male with Down syndrome, fragile X syndrome, and autismJ Dev Behav Pediatr31333337
Not in our library10.1097/dbp.0b013e3181d5aa56
30.
Berry-Kravis E Raspa M Loggin-Hester L Bishop E Holiday D D B Epilepsy in fragile X syndrome: characteristics and co-morbid diagnosesAm J Intellect Dev Disabil in press
Not in our library10.1352/1944-7558-115.6.461
31.
Leigh MJ Tassone F Mendoza-Morales G Nguyen D Boyd A Brodovsky J Ruiz C Hessl D Hagerman RJ Evaluation of autism spectrum disorders in females with Fragile X syndrome [abstract]International Meeting for Autism Research; 2010, May 20-22; Philadelphia, PA2010 375376Abstract # 118.169
Not in our library
32.
Bailey DB Jr Hatton DD Mesibov GB Ament N Skinner M Early development, temperament and functional impairment in autism and fragile X syndromeJ Autism Dev Disord2000 304959
Not in our library10.1023/a:1005412111706
33.
Bailey DB Jr Hatton DD Skinner M Mesibov GB Autistic behavior, FMR1 protein, and developmental trajectories in young males with fragile X syndromeJ Autism Dev Disord2001 31165174
Not in our library10.1023/a:1010747131386
34.
Loesch DZ Bui QM Dissanayake C Clifford S Gould E Bulhak-Paterson D Tassone F Taylor AK Hessl D Hagerman R Huggins RM Molecular and cognitive predictors of the continuum of autistic behaviours in fragile XNeurosci Biobehav Rev2007 31315326
Not in our library10.1016/j.neubiorev.2006.09.007
35.
Lewis P Abbeduto L Murphy M Richmond E Giles N Bruno L Schroeder S Anderson J Orsmond G Psychological well-being of mothers of youth with fragile X syndrome: syndrome specificity and within-syndrome variabilityJ Intellect Disabil Res2006 50894904
Not in our library10.1111/j.1365-2788.2006.00907.x
36.
Hagerman RJ Hagerman RJ, Hagerman PJPhysical and behavioral phenotypeFragile X syndrome: Diagnosis, treatment and research2002 3Baltimore: The Johns Hopkins University Press3109
Not in our library
37.
Hessl D Tassone F Cordeiro L Koldewyn K McCormick C Green C Wegelin J Yuhas J Hagerman RJ Brief report: aggression and stereotypic behavior in males with fragile X syndrome--moderating secondary genes in a "single gene" disorderJ Autism Dev Disord2008 38184189
Not in our library10.1007/s10803-007-0365-5
38.
Nowicki ST Tassone F Ono MY Ferranti J Croquette MF Goodlin-Jones B Hagerman RJ The Prader-Willi phenotype of fragile X syndromeJ Dev Behav Pediatr2007 28133138
Not in our library10.1097/01.dbp.0000267563.18952.c9
39.
Kenet T Froemke RC Schreiner CE Pessah IN Merzenich MM Perinatal exposure to a noncoplanar polychlorinated biphenyl alters tonotopy, receptive fields, and plasticity in rat primary auditory cortexProc Natl Acad Sci USA2007 10476467651
Not in our library10.1073/pnas.0701944104
40.
Waly M Olteanu H Banerjee R Choi SW Mason JB Parker BS Sukumar S Shim S Sharma A Benzecry JM Power-Charnitsky VA Deth RC Activation of methionine synthase by insulin-like growth factor-1 and dopamine: a target for neurodevelopmental toxins and thimerosalMol Psychiatry2004 9358370
Not in our library10.1038/sj.mp.4001476
41.
Maternal Residence Near Agricultural Pesticide Applications and Autism Spectrum Disorders among Children in the California Central Valley · 2007
No notice
42.
Paul R Pessah IN Gane L Ono M Hagerman PJ Brunberg JA Tassone F Bourgeois JA Adams PE Nguyen DV Hagerman R Early onset of neurological symptoms in fragile X premutation carriers exposed to neurotoxinsNeurotoxicology2010 31399402
Not in our library10.1016/j.neuro.2010.04.002
43.
Chen Y Tassone F Berman RF Hagerman PJ Hagerman RJ Willemsen R Pessah IN Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degenerationHum Mol Genet2010 19196208
Not in our library10.1093/hmg/ddp479
44.
Ross-Inta C Omanska-Klusek A Wong S Barrow C Garcia-Arocena D Iwahashi C Berry-Kravis E Hagerman RJ Hagerman PJ Giulivi C Mitochondrial dysfunction in fragile X-associated tremor/ataxia syndromeJ Biol Chem2010 42954552
Not in our library10.1042/bj20091960
45.
O'Dwyer JP Clabby C Crown J Barton DE Hutchinson M Fragile X-associated tremor/ataxia syndrome presenting in a woman after chemotherapyNeurology2005 65331332
Not in our library10.1212/01.wnl.0000168865.36352.53
46.
Qin M Kang J Burlin TV Jiang C Smith CB Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouseJ Neurosci2005 2550875095
Not in our library10.1523/jneurosci.0093-05.2005
47.
Darnell JC van Dreische S Zhang C Mele A Zang JB Fak JJ S-W C Richter J Darnell RB HITS-CLIP identifies specific neuronal mRNA targets of translational repression by the fragile X mental retardation protein, FMRP [abstract]Keystone Symposia; Snowbird, UT2010 56Abstract # 016
Not in our library
48.
Dahlhaus R El-Husseini A Altered neuroligin expression is involved in social deficits in a mouse model of the fragile X syndromeBehav Brain Res2010 20896105
Not in our library10.1016/j.bbr.2009.11.019
49.
Darnell JC Mostovetsky O Darnell RB FMRP RNA targets: identification and validationGenes Brain Behav2005 4341349
Not in our library10.1111/j.1601-183x.2005.00144.x
50.
Miyashiro KY Beckel-Mitchener A Purk TP Becker KG Barret T Liu L Carbonetto S Weiler IJ Greenough WT Eberwine J RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null miceNeuron2003 37417431
Not in our library10.1016/s0896-6273(03)00034-5
51.
Butler MG Dasouki MJ Zhou XP Talebizadeh Z Brown M Takahashi TN Miles JH Wang CH Stratton R Pilarski R Eng C Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutationsJ Med Genet2005 42318321
Not in our library10.1136/jmg.2004.024646
52.
Chiu S Wegelin JA Blank J Jenkins M Day J Hessl D Tassone F Hagerman R Early acceleration of head circumference in children with fragile x syndrome and autismJ Dev Behav Pediatr2007 283135
Not in our library10.1097/01.dbp.0000257518.60083.2d
53.
Nishimura Y Martin CL Vazquez-Lopez A Spence SJ Alvarez-Retuerto AI Sigman M Steindler C Pellegrini S Schanen NC Warren ST Geschwind DH Genome-wide expression profiling of lymphoblastoid cell lines distinguishes different forms of autism and reveals shared pathwaysHum Mol Genet2007 1616821698
Not in our library10.1093/hmg/ddm116
54.
Schenck A Bardoni B Langmann C Harden N Mandel JL Giangrande A CYFIP/Sra-1 controls neuronal connectivity in Drosophila and links the Rac1 GTPase pathway to the fragile X proteinNeuron2003 38887898
Not in our library10.1016/s0896-6273(03)00354-4
55.
Sharma A Hoeffer CA Takayasu Y Miyawaki T McBride SM Klann E Zukin RS Dysregulation of mTOR signaling in fragile X syndromeJ Neurosci2010 30694702
Not in our library10.1523/jneurosci.3696-09.2010
56.
Tassone F mTOR up-regulation in patients with FXS [abstract]FRAXA Investigators meeting May 2nd - 5th; Durham, NH2010
Not in our library
57.
de Vries PJ Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complexNeurotherapeutics2010 7275282
Not in our library10.1016/j.nurt.2010.05.001
58.
Hazlett HC Poe MD Lightbody AA Gerig G MacFall JR Ross AK Provenzale J Martin A Reiss AL Piven J Teasing apart the heterogeneity of autism: Same behavior, different brains in toddlers with fragile X syndrome and autismJ Neurodevelop Disord2009 18190
Not in our library10.1007/s11689-009-9009-8
59.
Hernandez RN Feinberg RL Vaurio R Passanante NM Thompson RE Kaufmann WE Autism spectrum disorder in fragile X syndrome: a longitudinal evaluationAm J Med Genet A2009 149A11251137
Not in our library10.1002/ajmg.a.32848
60.
Belmonte MK Bourgeron T Fragile X syndrome and autism at the intersection of genetic and neural networksNat Neurosci2006 912211225
Not in our library10.1038/nn1765
61.
Harlow EG Till SM Russell TA Wijetunge LS Kind P Contractor A Critical period plasticity is disrupted in the barrel cortex of FMR1 knockout miceNeuron65385398
Not in our library10.1016/j.neuron.2010.01.024
62.
Hoeft F Carter JC Lightbody AA Cody Hazlett H Piven J Reiss AL Region-specific alterations in brain development in one- to three-year-old boys with fragile X syndromeProc Natl Acad Sci USA2010 10793359339
Not in our library10.1073/pnas.1002762107
63.
Hagerman RJ Berry-Kravis E Kaufmann WE Ono MY Tartaglia N Lachiewicz A Kronk R Delahunty C Hessl D Visootsak J Picker J Gane L Tranfaglia M Advances in the treatment of fragile X syndromePediatrics2009 123378390
Not in our library10.1542/peds.2008-0317
64.
Amiri K Hagerman RJ Hagerman PJ Fragile X-associated tremor/ataxia syndrome: an aging face of the fragile X geneArch Neurol2008 651925
Not in our library10.1001/archneurol.2007.30
65.
Brouwer JR Willemsen R Oostra BA The FMR1 gene and fragile X-associated tremor/ataxia syndromeAm J Med Genet B Neuropsychiatr Genet2009 150B782798
Not in our library10.1002/ajmg.b.30910
66.
Dick KA Margolis JM Day JW Ranum LP Dominant non-coding repeat expansions in human diseaseGenome Dyn2006 16783full_text
Not in our library10.1159/000092501
67.
Tan H Li H Jin P RNA-mediated pathogenesis in fragile X-associated disordersNeurosci Lett2009 466103108
Not in our library10.1016/j.neulet.2009.07.053
68.
Garcia-Arocena D Hagerman PJ Advances in understanding the molecular basis of FXTASHum Mol Genet2010 19R8389
Not in our library10.1093/hmg/ddq166
69.
Hagerman PJ Hagerman RJ Fragile X-associated tremor/ataxia syndrome (FXTAS)Ment Retard Dev Disabil Res Rev2004 102530
Not in our library10.1002/mrdd.20005
70.
Berman RF Willemsen R Mouse models of fragile X-associated tremor ataxiaJ Investig Med2009 57837841
Not in our library
71.
Jin P Duan R Qurashi A Qin Y Tian D Rosser TC Liu H Feng Y Warren ST Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndromeNeuron2007 55556564
Not in our library10.1016/j.neuron.2007.07.020
72.
Sofola OA Jin P Qin Y Duan R Liu H de Haro M Nelson DL Botas J RNA-binding proteins hnRNP A2/B1 and CUGBP1 suppress fragile X CGG premutation repeat-induced neurodegeneration in a Drosophila model of FXTASNeuron2007 55565571
Not in our library10.1016/j.neuron.2007.07.021
73.
Willemsen R Hoogeveen-Westerveld M Reis S Holstege J Severijnen LA Nieuwenhuizen IM Schrier M van Unen L Tassone F Hoogeveen AT Hagerman PJ Mientjes EJ Oostra BA The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclear neuronal inclusions; implications for the cerebellar tremor/ataxia syndromeHum Mol Genet2003 12949959
Not in our library10.1093/hmg/ddg114
74.
Entezam A Biacsi R Orrison B Saha T Hoffman GE Grabczyk E Nussbaum RL Usdin K Regional FMRP deficits and large repeat expansions into the full mutation range in a new Fragile X premutation mouse modelGene2007 395125134
Not in our library10.1016/j.gene.2007.02.026
75.
Handa V Saha T Usdin K The fragile X syndrome repeats form RNA hairpins that do not activate the interferon-inducible protein kinase, PKR, but are cut by DicerNucleic Acids Res2003 3162436248
Not in our library10.1093/nar/gkg818
76.
Hashem V Galloway JN Mori M Willemsen R Oostra BA Paylor R Nelson DL Ectopic expression of CGG containing mRNA is neurotoxic in mammalsHum Mol Genet2009 1824432451
Not in our library10.1093/hmg/ddp182
77.
Jin P Zarnescu DC Zhang F Pearson CE Lucchesi JC Moses K Warren ST RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in DrosophilaNeuron2003 39739747
Not in our library10.1016/s0896-6273(03)00533-6
78.
Sofola OA Jin P Botas J Nelson DL Argonaute-2-dependent rescue of a Drosophila model of FXTAS by FRAXE premutation repeatHum Mol Genet2007 1623262332
Not in our library10.1093/hmg/ddm186
79.
Van Dam D Errijgers V Kooy RF Willemsen R Mientjes E Oostra BA De Deyn PP Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS)Behav Brain Res2005 162233239
Not in our library10.1016/j.bbr.2005.03.007
80.
Allen E He W Yadav-Shah M Sherman S A study of the distributional characteristics of FMR1 transcript levels in 238 individualsHuman Genetics2004 114439447
Not in our library10.1007/s00439-004-1086-x
81.
Kenneson A Zhang F Hagedorn CH Warren ST Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriersHum Mol Genet2001 1014491454
Not in our library10.1093/hmg/10.14.1449
82.
Hunter JE Rohr JK Sherman SL Co-occurring diagnoses among FMR1 premutation allele carriersClin Genet2010 77374381
Not in our library10.1111/j.1399-0004.2009.01317.x
83.
Sullivan AK Marcus M Epstein MP Allen EG Anido AE Paquin JJ Yadav-Shah M Sherman SL Association of FMR1 repeat size with ovarian dysfunctionHum Reprod2005 20402412
Not in our library10.1093/humrep/deh635
84.
Wittenberger MD Hagerman RJ Sherman SL McConkie-Rosell A Welt CK Rebar RW Corrigan EC Simpson JL Nelson LM The FMR1 premutation and reproductionFertil Steril2007 87456465
Not in our library10.1016/j.fertnstert.2006.09.004
85.
Greco CM Hagerman RJ Tassone F Chudley AE Del Bigio MR Jacquemont S Leehey M Hagerman PJ Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriersBrain2002 12517601771
Not in our library10.1093/brain/awf184
86.
Tassone F Iwahashi C Hagerman PJ FMR1 RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS)RNA Biol2004 1103105
Not in our library10.4161/rna.1.2.1035
87.
Bailey DB Jr Raspa M Olmsted M Holiday DB Co-occurring conditions associated with FMR1 gene variations: findings from a national parent surveyAm J Med Genet A2008 146A20602069
Not in our library10.1002/ajmg.a.32439
88.
Garcia-Arocena D Yang JE Brouwer JR Tassone F Iwahashi C Berry-Kravis EM Goetz CG Sumis AM Zhou L Nguyen DV Campos L Howell E Ludwig A Greco C Willemsen R Hagerman RJ Hagerman PJ Fibroblast phenotype in male carriers of FMR1 premutation allelesHum Mol Genet2010 19299312
Not in our library10.1093/hmg/ddp497
89.
Hunsaker MR Wenzel HJ Willemsen R Berman RF Progressive spatial processing deficits in a mouse model of the fragile X premutationBehav Neurosci2009 12313151324
Not in our library10.1037/a0017616
90.
Tassone F Adams J Berry-Kravis EM Cohen SS Brusco A Leehey MA Li L Hagerman RJ Hagerman PJ CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS)Am J Med Genet B Neuropsychiatr Genet2007 144566569
Not in our library10.1002/ajmg.b.30482
91.
Lee JE Cooper TA Pathogenic mechanisms of myotonic dystrophyBiochem Soc Trans2009 3712811286
Not in our library10.1042/bst0371281
92.
Wheeler TM Thornton CA Myotonic dystrophy: RNA-mediated muscle diseaseCurr Opin Neurol2007 20572576
Not in our library10.1097/wco.0b013e3282ef6064
93.
Arocena DG Iwahashi CK Won N Beilina A Ludwig AL Tassone F Schwartz PH Hagerman PJ Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cellsHum Mol Genet2005 1436613671
Not in our library10.1093/hmg/ddi394
94.
Sellier C Rau F Liu Y Tassone F Hukema RK Gattoni R Schneider A Richard S Willemsen R Elliott DJ Hagerman PJ Charlet-Berguerand N Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patientsEMBO J2010 2912481261
Not in our library10.1038/emboj.2010.21
95.
Sellier C Hagerman P Willemsen R Charlet-Berguerand N DROSHA/DGCR8 sequestration by expanded CGG repeats leads to global micro-RNA processing alteration in FXTAS patients [abstract]12th International Fragile X Conference; July 21-25; Detroit, MI2010
Not in our library
96.
Mah LJ El-Osta A Karagiannis TC gammaH2AX: a sensitive molecular marker of DNA damage and repairLeukemia2010 24679686
Not in our library10.1038/leu.2010.6
97.
Iwahashi CK Yasui DH An HJ Greco CM Tassone F Nannen K Babineau B Lebrilla CB Hagerman RJ Hagerman PJ Protein composition of the intranuclear inclusions of FXTASBrain2006 129256271
Not in our library10.1093/brain/awh650
98.
Oliveira G Diogo L Grazina M Garcia P Ataide A Marques C Miguel T Borges L Vicente AM Oliveira CR Mitochondrial dysfunction in autism spectrum disorders: a population-based studyDev Med Child Neurol2005 47185189
Not in our library10.1017/s0012162205000332
99.
Mitochondrial Disease in Autism Spectrum Disorder Patients: A Cohort Analysis · 2008
No notice
100.
Graf WD Marin-Garcia J Gao HG Pizzo S Naviaux RK Markusic D Barshop BA Courchesne E Haas RH Autism associated with the mitochondrial DNA G8363A transfer RNA(Lys) mutationJ Child Neurol2000 15357361
Not in our library10.1177/088307380001500601
101.
Pons R Andreu AL Checcarelli N Vila MR Engelstad K Sue CM Shungu D Haggerty R de Vivo DC DiMauro S Mitochondrial DNA abnormalities and autistic spectrum disordersJ Pediatr2004 1448185
Not in our library10.1016/j.jpeds.2003.10.023
102.
Filipek PA Juranek J Smith M Mays LZ Ramos ER Bocian M Masser-Frye D Laulhere TM Modahl C Spence MA Gargus JJ Mitochondrial dysfunction in autistic patients with 15q inverted duplicationAnn Neurol2003 53801804
Not in our library10.1002/ana.10596
103.
Hagerman RJ Staley LW O'Connor R Lugenbeel K Nelson D McLean SD Taylor A Learning-disabled males with a fragile X CGG expansion in the upper premutation size rangePediatrics1996 97122126
Not in our library
104.
Loesch DZ Hay DA Mulley J Transmitting males and carrier females in fragile X--revisitedAm J Med Genet1994 51392399
Not in our library10.1002/ajmg.1320510418
105.
Tassone F Hagerman RJ Taylor AK Mills JB Harris SW Gane LW Hagerman PJ Clinical involvement and protein expression in individuals with the FMR1 premutationAm J Med Genet2000 91144152
Not in our library10.1002/(sici)1096-8628(20000313)91:2<144::aid-ajmg14>3.0.co;2-v
106.
Aziz M Stathopulu E Callias M Taylor C Turk J Oostra B Willemsen R Patton M Clinical features of boys with fragile X premutations and intermediate allelesAm J Med Genet2003 121B119127
Not in our library10.1002/ajmg.b.20030
107.
Clifford S Dissanayake C Bui QM Huggins R Taylor AK Loesch DZ Autism spectrum phenotype in males and females with fragile X full mutation and premutationJ Autism Dev Disord2007 37738747
Not in our library10.1007/s10803-006-0205-z
108.
Farzin F Perry H Hessl D Loesch D Cohen J Bacalman S Gane L Tassone F Hagerman P Hagerman R Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutationJ Dev Behav Pediatr2006 27S137144
Not in our library10.1097/00004703-200604002-00012
109.
Loesch DZ Cook M Litewka L Gould E Churchyard A Tassone F Slater HR Storey E A low symptomatic form of neurodegeneration in younger carriers of the FMR1 premutation, manifesting typical radiological changesJ Med Genet2008 45179181
Not in our library10.1136/jmg.2007.054171
110.
Hashimoto RI Backer KC Tassone F Hagerman RJ Rivera SM An fMRI study of the prefrontal activity during the performance of a working memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FXTAS)J Psychiatr Res2010
Not in our library10.1016/j.jpsychires.2010.04.030
111.
Hashimoto R Srivastava S Tassone F Hagerman RJ Rivera SM Diffusion tensor imaging in male premutation carriers of the fragile X mental retardation geneMovement Disord in press
Not in our library10.1002/mds.23646
112.
Loesch DZ Bui QM Grigsby J Butler E Epstein J Huggins RM Taylor AK Hagerman RJ Effect of the fragile X status categories and the fragile X mental retardation protein levels on executive functioning in males and females with fragile XNeuropsychology2003 17646657
Not in our library10.1037/0894-4105.17.4.646
113.
Grigsby J Brega AG Engle K Leehey MA Hagerman RJ Tassone F Hessl D Hagerman PJ Cogswell JB Bennett RE Cook K Hall DA Bounds LS Paulich MJ Reynolds A Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndromeNeuropsychology2008 224860
Not in our library10.1037/0894-4105.22.1.48
114.
Moore CJ Daly EM Schmitz N Tassone F Tysoe C Hagerman RJ Hagerman PJ Morris RG Murphy KC Murphy DG A neuropsychological investigation of male premutation carriers of fragile X syndromeNeuropsychologia2004 4219341947
Not in our library10.1016/j.neuropsychologia.2004.05.002
115.
Cornish KM Li L Kogan CS Jacquemont S Turk J Dalton A Hagerman RJ Hagerman PJ Age-dependent cognitive changes in carriers of the fragile X syndromeCortex2008 44628636
Not in our library10.1016/j.cortex.2006.11.002
116.
Cornish KM Kogan CS Li L Turk J Jacquemont S Hagerman RJ Lifespan changes in working memory in fragile X premutation malesBrain Cogn2009 69551558
Not in our library10.1016/j.bandc.2008.11.006
117.
Kogan CS Cornish KM Mapping self-reports of working memory deficits to executive dysfunction in fragile X mental retardation 1 (FMR1) gene premutation carriers asymptomatic for FXTASBrain Cogn2010 73236243
Not in our library10.1016/j.bandc.2010.05.008
118.
Hunter JE Allen EG Abramowitz A Rusin M Leslie M Novak G Hamilton D Shubeck L Charen K Sherman SL No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50Am J Hum Genet2008 83692702
Not in our library10.1016/j.ajhg.2008.10.021
119.
Grigsby J Hills J Wilson R Leehey M Hagerman RJ Tassone F Hagerman PJ Dysexecutive syndrome in older men with action tremor and the fragile X premutationJ Int Neuropsychol Soc2002 8282
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121.
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Not in our library10.1097/ypg.0b013e3282f97e0b
122.
Franke P Leboyer M Gansicke M Weiffenbach O Biancalana V Cornillet-Lefebre P Croquette MF Froster U Schwab SG Poustka F Hautzinger M Maier W Genotype-phenotype relationship in female carriers of the premutation and full mutation of FMR-1Psychiatry Res1998 80113127
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123.
Hessl D Tassone F Loesch DZ Berry-Kravis E Leehey MA Gane LW Barbato I Rice C Gould E Hall DA Grigsby J Wegelin JA Harris S Lewin F Weinberg D Hagerman PJ Hagerman RJ Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutationAm J Med Genet B Neuropsychiatr Genet2005 139B115121
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Bourgeois J Seritan A Casillas E Hessl D Schneider A Yang Y Kaur I Cogswell J Nguyen D Hagerman R Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriersJ Clin Psychiatry2010 10.4088/JCP.4009m05407blu
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Rodriguez-Revenga L Madrigal I Pagonabarraga J Xuncla M Badenas C Kulisevsky J Gomez B Mila M Penetrance of FMR1 premutation associated pathologies in fragile X syndrome familiesEur J Hum Genet2009 1713591362
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Zhang L Coffey S Lua LL Greco CM Schafer JA Brunberg J Borodyanskaya M Agius MA Apperson M Leehey M Tartaglia N Tassone F Hagerman PJ Hagerman RJ FMR1 premutation in females diagnosed with multiple sclerosisJ Neurol Neurosurg Psychiatry2009 80812814
Not in our library10.1136/jnnp.2008.160960
127.
Greco CM Tassone F Garcia-Arocena D Tartaglia N Coffey SM Vartanian TK Brunberg JA Hagerman PJ Hagerman RJ Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosisArch Neurol2008 6511141116
Not in our library10.1001/archneur.65.8.1114
128.
Chonchaiya W Tassone F Ashwood P Hessl D Schneider A Campos L Nguyen D Au J Hagerman R Autoimmune disease in mothers with the FMR1 premutation is associated with seizures in their children with fragile X syndromeJ Hum Genet in press
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Penagarikano O Mulle JG Warren ST The pathophysiology of fragile X syndromeAnnu Rev Genomics Hum Genet2007 8109129
Not in our library10.1146/annurev.genom.8.080706.092249
131.
Bassell GJ Warren ST Fragile X syndrome: loss of local mRNA regulation alters synaptic development and functionNeuron2008 60201214
Not in our library10.1016/j.neuron.2008.10.004
132.
Fragile X Mental Retardation Protein Regulates Proliferation and Differentiation of Adult Neural Stem/Progenitor Cells · 2010
No notice
133.
Utari A Adams E Berry-Kravis E Chavez A Scaggs F Ngotran L Boyd A Hessl D Gane LW Tassone F Tartaglia N Leehey MA Hagerman RJ Aging in fragile X syndromeJ Neurodev Disord2010 27076
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134.
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135.
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136.
Dolen G Bear MF Role for metabotropic glutamate receptor 5 (mGluR5) in the pathogenesis of fragile X syndromeJ Physiol2008 58615031508
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137.
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141.
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145.
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Not in our library10.1016/j.neuron.2007.12.001
146.
Bear MF Therapeutic implications of the mGluR theory of fragile X mental retardationGenes Brain Behav2005 4393398
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147.
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148.
Yan QJ Rammal M Tranfaglia M Bauchwitz RP Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEPNeuropharmacology2005 4910531066
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149.
de Vrij FM Levenga J van der Linde HC Koekkoek SK De Zeeuw CI Nelson DL Oostra BA Willemsen R Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO miceNeurobiol Dis2008 31127132
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150.
Bauchwitz RP Yan Q Rammal M Modulation of mGluR5 activity in vivo can ameliorate phenotypic markers of fragile X syndrome in miceSociety for Neuroscience; October 23-27; San Diego, CA2004 Society for Neuroscience583.520
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Not in our library10.1016/j.neuron.2005.01.038
152.
A pilot open label, single dose trial of fenobam in adults with fragile X syndrome · 2009
No notice
153.
Wang LW Berry-Kravis E Hagerman RJ Fragile X: leading the way for targeted treatments in autismNeurotherapeutics2010 7264274
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154.
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155.
Scanziani M Capogna M Gahwiler BH Thompson SM Presynaptic inhibition of miniature excitatory synaptic currents by baclofen and adenosine in the hippocampusNeuron1992 9919927
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156.
Sohn JW Lee D Cho H Lim W Shin HS Lee SH Ho WK Receptor-specific inhibition of GABAB-activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampusJ Physiol2007 580411422
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157.
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Not in our library10.1124/jpet.108.143990
158.
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Not in our library10.1124/mol.109.056127
159.
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160.
Mihalek RM Banerjee PK Korpi ER Quinlan JJ Firestone LL Mi ZP Lagenaur C Tretter V Sieghart W Anagnostaras SG Sage JR Fanselow MS Guidotti A Spigelman I Li Z DeLorey TM Olsen RW Homanics GE Attenuated sensitivity to neuroactive steroids in gamma-aminobutyrate type A receptor delta subunit knockout miceProc Natl Acad Sci USA1999 961290512910
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161.
Carter RB Wood PL Wieland S Hawkinson JE Belelli D Lambert JJ White HS Wolf HH Mirsadeghi S Tahir SH Bolger MB Lan NC Gee KW Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3alpha-hydroxy-3beta-methyl-5alpha-pregnan-20-one), a selective, high-affinity, steroid modulator of the gamma-aminobutyric acid(A) receptorJ Pharmacol Exp Ther1997 28012841295
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162.
Bormann J The 'ABC' of GABA receptorsTrends Pharmacol Sci2000 211619
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163.
Chebib M Johnston GA The 'ABC' of GABA receptors: a brief reviewClin Exp Pharmacol Physiol1999 26937940
Not in our library10.1046/j.1440-1681.1999.03151.x
164.
D'Hulst C Kooy RF The GABAA receptor: a novel target for treatment of fragile X?Trends Neurosci2007 30425431
Not in our library10.1016/j.tins.2007.06.003
165.
Miyashiro KY Beckel-Mitchener A Purk TP Becker KG Barret T Liu L Carbonetto S Weiler IJ Greenough WT Eberwine J RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null miceNeuron2003 37417431
Not in our library10.1016/s0896-6273(03)00034-5
166.
Chang S Bray SM Li Z Zarnescu DC He C Jin P Warren ST Identification of small molecules rescuing fragile X syndrome phenotypes in DrosophilaNat Chem Biol2008 4256263
Not in our library10.1038/nchembio.78
167.
D'Hulst C De Geest N Reeve SP Van Dam D De Deyn PP Hassan BA Kooy RF Decreased expression of the GABAA receptor in fragile X syndromeBrain Res2006 1121238245
Not in our library10.1016/j.brainres.2006.08.115
168.
Gantois I Vandesompele J Speleman F Reyniers E D'Hooge R Severijnen LA Willemsen R Tassone F Kooy RF Expression profiling suggests underexpression of the GABA(A) receptor subunit delta in the fragile X knockout mouse modelNeurobiol Dis2006 21346357
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169.
Selby L Zhang C Sun QQ Major defects in neocortical GABAergic inhibitory circuits in mice lacking the fragile X mental retardation proteinNeurosci Lett2007 412227232
Not in our library10.1016/j.neulet.2006.11.062
170.
D'Hulst C Heulens I Brouwer JR Willemsen R De Geest N Reeve SP De Deyn PP Hassan BA Kooy RF Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS)Brain Research2009 1253176183
Not in our library10.1016/j.brainres.2008.11.075
171.
Curia G Papouin T Seguela P Avoli M Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndromeCereb Cortex2009 1915151520
Not in our library10.1093/cercor/bhn159
172.
El Idrissi A Ding XH Scalia J Trenkner E Brown WT Dobkin C Decreased GABA(A) receptor expression in the seizure-prone fragile X mouseNeurosci Lett2005 377141146
Not in our library10.1016/j.neulet.2004.11.087
173.
Kooy RF Of mice and the fragile X syndromeTrends Genet2003 19148154
Not in our library10.1016/s0168-9525(03)00017-9
174.
D'Antuono M Merlo D Avoli M Involvement of cholinergic and gabaergic systems in the fragile X knockout miceNeuroscience2003 119913
Not in our library10.1016/s0306-4522(03)00103-9
175.
Kooy F Heulens I D'Hulst C Van der Aa N Bagni C Hassan B De Deyn P The GABAA receptor as a potential target for therapy of the fragile X syndrome [abstract]NFXF 12th International FX Conference; July 21 - 25; Detroit, MI2010
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176.
Reddy DS Pharmacology of endogenous neuroactive steroidsCrit Rev Neurobiol2003 15197234
Not in our library10.1615/critrevneurobiol.v15.i34.20
177.
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178.
Rogawski MA Reddy DS Rho JM, Sankar R, Cavazos JNeurosteroids: endogenous modulators of seizure susceptibilityEpilepsy: Scientific Foundations of Clinical Practice2004 New York: Marcel Dekker319355
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179.
Laxer K Blum D Abou-Khalil BW Morrell MJ Lee DA Data JL Monaghan EP Assessment of ganaxolone's anticonvulsant activity using a randomized, double-blind, presurgical trial design. Ganaxolone Presurgical Study GroupEpilepsia2000 4111871194
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180.
Kerrigan JF Shields WD Nelson TY Bluestone DL Dodson WE Bourgeois BF Pellock JM Morton LD Monaghan EP Ganaxolone for treating intractable infantile spasms: a multicenter, open-label, add-on trialEpilepsy Res2000 42133139
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181.
Bilousova TV Rusakov DA Ethell DW Ethell IM Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activationJ Neurochem2006 974456
Not in our library10.1111/j.1471-4159.2006.03701.x
182.
Utari A Chonchaiya W Rivera SM Schneider A Hagerman RJ Faradz SM Ethell IM Nguyen DV Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measuresAm J Intellect Dev Disabil2010 115433443
Not in our library10.1352/1944-7558-115.5.433
183.
Open-label add-on treatment trial of minocycline in fragile X syndrome · 2010
No notice

Cited by papers we hold 3

Local Translation in Nervous System Pathologies · 2021
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Heterogeneity within Autism Spectrum Disorders: What have We Learned from Neuroimaging Studies? · 2013
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Neural circuit architecture defects in a Drosophila model of Fragile X syndrome are alleviated by minocycline treatment and genetic removal of matrix metalloproteinase · 2011
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