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Cited by 321Genetics and Neurodevelopmental DisordersGenetic Neurodegenerative DiseasesDown syndrome and intellectual disability research

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

Open access
Bagni, Claudia, Tassone, Flora, Neri, Giovanni, Hagerman, Randi·2012·Journal of Clinical Investigation
DOI 10.1172/jci63141PMC PMC3533539
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Abstract

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.Conflict of interest: Randi Hagerman has received grant support from Roche, Novartis, Seaside Therapeutics, Forest, and Curemark to carry out clinical trials for fragile X and/or ASD.She has also consulted with Novartis regarding clinical trials in fragile X syndrome.Giovanni

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Crossref · 10.1172/jci63141

Cites

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Claims the paper makes

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  • Premisecitation

    FMR1 silencing is the consequence of complex epigenetic modifications.

    “FMR1 silencing is the consequence of rather complex epigenetic modifications (13).”
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    • cites [13] source

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  • Premisecitation

    The risk of premutation-to-full-mutation transition depends on CGG repeat size, with nearly 100% risk for alleles over 99 repeats.

    “The risk of a PM to FM transition depends on the CGG repeat size, such that the expansion risk is nearly 100% for alleles of >99 CGG repeats (11).”
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    • cites [11] source

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  • Premisecitation

    The number of AGG interruptions in the CGG repeat correlates inversely with the risk of expansion to a full mutation in the next generation.

    “A recent study (12) showed that the number of AGG interruptions present in the CGG repeats correlates inversely with the risk of expansion to a FM in the next generation.”
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    • cites [12] Yrigollen, 2012, Genet Med. source

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  • Premisecitation

    In fragile X syndrome, cytosines up to about 1 kb upstream of the CGG repeats, including the FMR1 promoter, are methylated.

    “In FXS, cytosines located approximately up to 1-kb upstream of the CGG repeat sequences, including the FMR1 promoter, are methylated (14,15).”
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  • Interpretationcitation

    AGG interruptions, together with CGG length, may better define the risk of transmission from a maternal premutation to a full mutation in offspring.

    “The presence of AGG interruptions, in addition to the CGG length, may thus better define the risk for transmission from a maternal PM to FM in the offspring.”
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  • Classified as probably not a substantial claim. 7
  • The quote only partly states this claim. 1

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    Premisecitation

    FMR1 was identified in 1991 by positional cloning and contains a polymorphic CGG triplet in its 5′ UTR.

    “Identified in 1991 by positional cloning (8), the FMR1 gene is characterized by the presence of a polymorphic CGG triplet sequence in the 5′ UTR (8, 9).”
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    Premisecitation

    Only about one-third of women with a full mutation have intellectual disability; most have normal IQ, although learning and emotional problems are common.

    “Due to compensation by the unaffected X chromosome, only one-third of female carriers with a full mutation (FM) have ID; the majority have normal IQ, although learning difficulties and emotional problems are common (7).”
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    • cites [7] source

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    Premisenone given

    Normal FMR1 alleles have 5 to 54 CGG repeats, with a mode of 30.

    “Normal alleles have a number of CGG repeats, ranging from 5 to 54, with a mode of 30.”
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    Premisereasoning

    Expansion of the CGG triplet causes fragile X syndrome, the prototype of unstable triplet expansion disorders.

    “Expansion in this triplet sequence gives rise to FXS, which is the prototype of unstable triplet expansion disorders.”
    Quote in the paperSubstantial claim

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    Premisecitation

    In full mutation alleles, this boundary is missing and cytosines upstream of the CGG repeat become methylated around the thirteenth week of embryonic development.

    “This boundary is missing in FM alleles, and the cytosines upstream of the CGG repeat become methylated around the thirteenth week of embryonic development (16).”
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    • cites [16] source

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    Premisenone given

    Normal alleles are methylated in the FMR1 promoter but not near the CGG repeat, which appears to be a boundary preventing methylation spread.

    “Normal alleles are also methylated in the FMR1 promoter region but not in close proximity to the CGG repeat, which seems to be a “boundary” in the normal allele that prevents methylation from spreading.”
    Quote in the paperNot a substantial claim

  • Probably not a substantial claim: may not pass S3 (load-bearing). May combine two claims.

    Premisecitation

    Fragile X syndrome affects roughly 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women.

    “Estimates report that FXS affects approximately 1 in 2,500 to 5,000 men and 1 in 4,000 to 6,000 women (2, 3).”
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    Premisecitation

    Fragile X syndrome is caused by mutations in FMR1, which lies on the X chromosome at Xq27.3 and coincides with the folate-sensitive fragile site.

    “FXS is caused by mutations in the FMR1 gene, which is located on the X chromosome and whose locus at Xq27.3 coincides with the folate-sensitive fragile site (4, 5).”
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    • cites [4] Fryns, 1984, Acta Paediatr Scand Suppl.

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    • cites [5] source

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    Premisenone given

    Premutation alleles have 55 to 200 CGG repeats.

    “Premutation (PM) alleles have a number of CGG repeats, ranging from 55 to 200.”
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    Premisecitation

    FMRP is detected in P bodies and stress granules, where it forms translationally silent preinitiation complexes.

    “FMRP has been detected in P bodies and stress granules as well, where it forms translationally silent preinitiation complexes (64) (Figure 2).”
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    • cites [64] source

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    Premisecitation

    These epigenetic changes promote a heterochromatic configuration that excludes specific transcription factors and turns gene expression off.

    “These epigenetic changes promote a heterochromatic configuration that excludes the binding of specific transcription factors (19), thus turning gene expression off (20).”
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    • cites [19] source

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    Premisecitation

    High-throughput screenings and accompanying small-scale studies show that many neuronal mRNAs, especially those encoding presynaptic and postsynaptic proteins, are deregulated in the absence of FMRP, suggesting that concerted alteration of many proteins contributes to the fragile X syndrome phenotype.

    “High-throughput screenings supported by accompanying small scale studies have revealed that a wide array of neuronal mRNAs, with a large proportion encoding for presynaptic and postsynaptic proteins, is deregulated in the absence of FMRP, suggesting that concerted alteration of many proteins contributes to the FXS phenotype (62).”
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    • cites [62] De Rubeis, 2012, Adv Exp Med Biol. source

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    Premisecitation

    Fragile X alleles show deacetylation of histones H3 and H4, reduced methylation of lysine 4, and increased methylation of lysine 9 on histone H3.

    “In addition to altered methylation status, FXS alleles show deacetylation of histones H3 and H4, reduced methylation of lysine 4 (K4), and increased methylation of lysine 9 (K9) on histone H3 (18).”
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    • cites [18] source

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    Premisenone given

    Some alleles remain partially or fully unmethylated despite having more than 200 CGG repeats, but the reasons for differences in methylation status are poorly understood.

    “Of note, some alleles remain partially or even fully unmethylated (UFM), despite containing >200 CGG repeats, but the differences in methylation status are poorly understood.”
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    Premisecitation

    Boys with fragile X syndrome typically show ADHD with impulsivity and anxiety, repetitive language, hand biting, hand stereotypies, rocking, and sometimes head banging.

    “The behavior of boys with FXS typically includes attention deficit hyperactivity disorder (ADHD), with significant impulsivity and anxiety, as well as behaviors that include repetitive language, hand biting, hand stereotypies, rocking, and sometimes head banging (24,25).”
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    • cites [25] Sullivan, 2006, Am J Med Genet A. source

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    Interpretationreasoning

    An imbalance between excitatory and inhibitory synaptic pathways may contribute to the hyperaroused clinical phenotype often seen in children with fragile X syndrome.

    “A child with FXS is often described as hyperaroused; an imbalance of the excitatory and inhibitory synaptic pathways described in the “From RNA metabolism to synaptic receptor dysfunction” section may contribute to such a clinical phenotype.”
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    Premisecitation

    FMRP is an RNA-binding protein, and only its cytoplasmic function has been well characterized.

    “FMRP is an RNA-binding protein, and, despite its clear shuttling from the nucleus to the cytoplasm (59,60), only the cytoplasmic function of FMRP has been well characterized.”
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    • cites [59] source

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    Premisecitation

    In unmethylated full mutation alleles, H3 and H4 acetylation and H3K9 methylation resemble full mutation alleles, while H3K4 and H3K27 methylation resemble normal alleles.

    “acetylation of histones H3 and H4 and methylation of lysine 9 on H3 of UFM alleles are more similar to those of FM alleles, while the level of methylation of lysines 4 and 27 on H3 are more similar to that of normal alleles (18,22).”
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    Premisecitation

    Premutation prevalence differs across ethnic groups, being higher in people of mixed European descent than in African American and Hispanic people, and is higher than in previous studies.

    “PM prevalence was found to be different in various ethnic groups; it was higher in people of mixed European descent compared with that in African American and Hispanic people (for both males and females) and shows a higher incidence for PM compared with that in previous studies (34,35).”
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    • cites [34] source

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    Premisecitation

    FMRP regulates stability, subcellular transport, and translation of neuronal mRNAs encoding proteins involved in synaptic structure and function.

    “FMRP regulates stability, subcellular transport, and translation of neuronal mRNAs encoding for proteins involved the in synaptic structure and function (58,(65)(66)(67).”
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    • cites [58] source

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    Premisecitation

    The fragile X mutation is the most common single genetic cause of autism, occurring in 1% to 6% of boys with autism spectrum disorder.

    “The fragile X mutation is the most common single genetic cause of autism, occurring in 1% to 6% of boys with ASD (7).”
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    • cites [7] source

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    Premisenone given

    Before age 2, children with fragile X syndrome may have hypotonia, delayed motor milestones, hand flapping, poor eye contact, frequent emesis or otitis media, and irritability.

    “Among the recurrent problems that may occur in children before 2 years of age are hypotonia, delayed motor milestones, hand flapping, poor eye contact, frequent emesis and/or otitis media, and irritability.”
    Quote in the paperNot a substantial claim

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    Premisenone given

    Most women with a full mutation do not have intellectual disability and are often diagnosed after their children are diagnosed with fragile X syndrome.

    “In addition, the majority of women with FM often do not have ID, and they are frequently diagnosed with FM following the diagnosis of FXS in their children.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Methylation inhibits FMR1 transcription, leading to absence of the FMRP protein product.

    “As a consequence, gene transcription is inhibited, leading to the absence of its protein product FMRP (17).”
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    • cites [17] source

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    Premisecitation

    In a US pilot newborn screening study of 11,217 newborns, the observed prevalence of a premutation was 1:188 in females and 1:480 in males, while gray-zone allele prevalence was 1:70 in females and 1:107 in males.

    “The results of a pilot newborn screening (NBS) study for FXS in the United States, based on the screening of 11,217 newborns, indicated that the observed prevalence of a PM allele is 1:188 in females and 1:480 in males, while the prevalence of gray-zone alleles (45-54 CGG repeats) is 1:70 in females and 1:107 in males (33).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [33] Tassone F, et al. Newborn screening in fragile X syndrome: prevalence and allele distribution of the FMR1 gene. Paper presented at: American College of Medical Genetics Annual Clinical Genetics Meeting; July 26, 2012; Charlotte, North Carolina, USA. http://www.fragilex.org/community/international-fragile-x-conference/miami2012/agenda/ . Accessed October 19, 2012.

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  • Probably not a substantial claim: may not pass S3 (load-bearing).

    Premisecitation

    FXTAS affects approximately 46% of male and 17% of female adult premutation carriers.

    “FXTAS (Figure 1) has been reported to affect approximately 46% of male and 17% of female adult carriers (28).”
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  • May combine two claims.

    Premisenone given

    About 30% of boys with fragile X syndrome meet diagnostic criteria for autism, and these children have the lowest developmental and adaptive behavior scores among those with fragile X syndrome.

    “Approximately 30% of boys with FXS meet the diagnostic criteria for autism, and these children have the lowest developmental and adaptive behavior scores of those with FXS.”
    Quote in the paperNot a substantial claim

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    Premisecitation

    Late diagnosis may occur in older patients tested before the 1991 discovery of FMR1 or in patients with mild or atypical disease, as often occurs with unmethylated full mutation alleles.

    “A late diagnosis may occur for older patients who may have undergone genetic testing prior to the 1991 discovery of the FMR1 gene (8) or for patients that carry a mild form of the disease, showing atypical symptoms as often occurs for the UFM alleles.”
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    Premisenone given

    Effects of 5-azadC on other methylated genes cannot be excluded.

    “effects on other methylated genes cannot be excluded.”
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    Premisecitation

    STEP is upregulated in fragile X syndrome, and genetic reduction of STEP diminished seizures and restored selected social and nonsocial anxiety-related behaviors in Fmr1 knockout mice.

    “Recently, the striatal enriched protein tyrosine phosphatase (STEP) has been shown to be upregulated in FXS, and genetic reduction of STEP diminished seizures and restored selected social and nonsocial anxiety-related behaviors in the Fmr1 KO mice (94).”
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    • cites [94] Goebel-Goody, 2012, Genes Brain Behav. source

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    Premisecitation

    The action of 5-azadC appears specific to the FMR1 gene, as shown by its lack of effect on the methylated sequence upstream of the FMR1 boundary.

    “While the action of 5-azadC appears to be specific in the context of the FMR1 gene, as shown by its lack of effect on the methylated sequence upstream of the FMR1 boundary (G.Neri, unpublished observations), effects on other methylated genes cannot be excluded.”
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    • cites G.Neri, unpublished observations

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    Premisecitation

    Molecular signaling pathways that orchestrate protein synthesis, spine shape, and synaptic plasticity, such as mTOR and ERK, are impaired in fragile X syndrome, possibly because some FMRP target mRNAs encode members of second messenger cascades converging on ERK.

    “The molecular signaling pathways orchestrating protein synthesis, spine shape, and synaptic plasticity, such as mTOR and ERK (Figure 2), are also impaired in FXS (72,(87)(88)(89), possibly because some FMRP target mRNAs encode members of second messenger cascades converging on ERK (88,89).”
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    • cites [87] Hoeffer, 2012, Genes Brain Behav. source

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  • Probably not a substantial claim: may not pass S4 (based). May combine two claims.

    Premisenone given

    5-azadC is presumed to be effective only on dividing cells, which excludes postmitotic neurons.

    “Moreover, it is presumed to be effective only on dividing cells, which excludes postmitotic neurons.”
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    • The authors state this as an assumption: 5-aza-deoxycytidine is effective only on dividing cells, so it would not act on postmitotic neurons.

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    Premisecitation

    In boys with fragile X syndrome, acetyl-l-carnitine produced significant amelioration of hyperactivity and adaptive behavior compared with placebo, but did not change FMR1 methylation state or increase gene expression.

    “A significant amelioration of the hyperactivity and adaptive behavior of drug-treated boys (compared with those treated with placebo) was observed; however, the methylation state of FMR1 did not change, and the expression of the gene did not increase (100).”
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    • cites [100] Torrioli, 2008, Am J Med Genet A. source

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    Premisereasoning

    This receptor imbalance results in enhanced mGluR-long-term depression, the most commonly studied form of hippocampal synaptic plasticity.

    “This receptor unbalance results in enhanced mGluR-long-term depression (mGluR-LTD), the most commonly studied forms of hippocampal synaptic plasticity.”
    Quote in the paperSubstantial claim

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    Premisecitation

    Expression of a dominant-negative PAK mutant in the forebrain of Fmr1 knockout mice improved behavioral abnormalities such as impaired locomotor activity, stereotypical anxiety, and trace fear conditioning, suggesting PAK signaling is a therapeutic target.

    “Expression of a dominant-negative mutant of PAK in the forebrain of Fmr1 KO mice led to an improvement of several behavioral abnormalities, such as impaired locomotor activity, stereotypical anxiety, and trace fear conditioning, suggesting that the PAK signaling pathway could also represent a bona fide site for therapeutic intervention (93).”
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    Premisecitation

    Reactivation by 5-azadC was accompanied by DNA demethylation and changes in the epigenetic code of histones H3 and H4.

    “Reactivation was accompanied not only by DNA demethylation but also by changes in the epigenetic code of histones H3 and H4 (97).”
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    Premisecitation

    Upon receptor activation, the FMRP-mediated translational block is released, possibly due to changes in phosphorylation status, and protein synthesis ensues.

    “Upon receptor activation, the FMRPmediated translational block is released, possibly due to changes (86) in its phosphorylation status, and protein synthesis can ensue.”
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  • Classified as probably not a substantial claim.

    Interpretationreasoning

    Because STEP acts on ERK1/2, NMDA, and AMPA, which are affected in fragile X syndrome, inhibiting STEP may be considered for treating patients with fragile X syndrome.

    “Because STEP acts on at least three molecules (ERK1/2, NMDA, and AMPA) affected in FXS, strategies to inhibit STEP activity may be considered for treating patients with FXS.”
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    • cites [94] Goebel-Goody, 2012, Genes Brain Behav. source

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    Interpretationcitation

    Because both mouse models have upregulated mTOR pathway activity, normal synaptic plasticity and cognition may occur within an optimal range of mGluR-mediated protein synthesis, such that deviations in either direction can lead to shared behavioral impairments.

    “Because both mouse models have upregulated mTOR pathway activity, the authors propose that normal synaptic plasticity and cognition occur within an optimal range of mGluRmediated protein synthesis, such that deviations in either direction can lead to shared behavioral impairments.”
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    • cites [92] source

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    Premisecitation

    Elevation of mGluR1 and mGluR5 and reduced insertion of AMPA receptors into the postsynaptic membrane are central mechanisms of impaired synaptic plasticity in fragile X syndrome and form the basis of mGluR theory.

    “Elevation of the glutamate receptors mGluR1 and mGluR5 and the reduced insertion of AMPA receptors into the postsynaptic membrane are two of the central mechanics of impaired synaptic plasticity in FXS: such a dysregulated signaling is the basis of mGluR theory (75).”
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    Premisenone given

    The strategy of restoring FMR1 gene activity is based on the presence of an intact FMR1 coding sequence and targets potentially reversible epigenetic changes, primarily DNA methylation.

    “The strategy of restoring FMR1 gene activity, which is based on the presence of the intact FMR1 coding sequence, targets potentially reversible epigenetic changes, primarily DNA methylation.”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The FMR1 coding sequence remains intact in fragile X syndrome cells, so restoring gene activity is feasible.

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    Premisecitation

    FMRP activity is regulated in response to metabotropic glutamate receptors, AMPA receptors, GABA receptors, NMDA receptors, and TrkB receptors.

    “FMRP activity is regulated in response to metabotropic glutamate receptors (mGluRs) (78), 2-amino-3-(5-methyl-3-oxo-1,2-oxazol-4-yl) propanoic acid (AMPA) receptors (79), γ-aminobutyric acid (GABA) receptors (76,80,81), N-methyl-d-aspartate (NMDA) receptors (82)(83)(84), and the tyrosine kinase or BDNF/NT-3 growth factor (TrkB) receptors (85).”
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  • May combine two claims.

    Premisenone given

    Two possible approaches for substantial fragile X syndrome treatment are reactivation of the affected gene and compensating for the lack of FMRP.

    “Two possible approaches are presently being considered for a substantial treatment of FXS: (a) reactivation of the affected gene and (b) compensating for the lack of FMRP.”
    Quote in the paperSubstantial claim

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    Interpretationreasoning

    Because the mouse model recapitulates morphological changes and behavioral deficits seen in human patients, molecular insights from it have led clinicians to design targeted treatments.

    “Because the mouse model recapitulates morphological changes and behavioral deficits seen in human patients, these molecular insights have led clinicians to design targeted treatments (see below).”
    Quote in the paperSubstantial claim
    • Rests on an assumption: The Fmr1 knockout mouse model reproduces the morphological and behavioral features of human fragile X syndrome closely enough that molecular findings in it can guide targeted treatments for patients.

  • May combine two claims.

    Premisenone given

    In the absence of FMRP, synthesis of proteins involved in cytoskeleton remodeling and receptor internalization such as Arc increases, while other proteins such as GABA receptor subunits decrease due to reduced mRNA stability.

    “In the absence of FMRP, there is an increase in the synthesis of several proteins involved in cytoskeleton remodeling and receptor internalization (i.e., Arc) (Figure 2) as well as reduction of other proteins due to a reduced stability of their mRNAs (i.e., GABA-R subunits).”
    Quote in the paperSubstantial claim

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    Premisecitation

    Crossing Grm5 heterozygous mice with Fmr1 knockout mice, producing a 50% reduction in mGluR5 protein, corrected typical fragile X syndrome phenotypic features including spine dysmorphogenesis and audiogenic seizures, and restored mGluR-long-term depression.

    “The resulting 50% reduction in mGluR5 protein levels in the offspring led to the correction of typical FXS phenotypic features, including spine dysmorphogenesis and audiogenic seizures, and restored mGluR-LTD (90).”
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    • cites [90] source

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    Premisecitation

    The GABA receptor system is downregulated in fragile X syndrome, partially due to destabilization of mRNAs encoding GABA receptor subunits.

    “The GABA receptor system has also been reported as downregulated in FXS, partially due to destabilization of the mRNAs encoding the GABA receptor subunits (76,80,113).”
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    • cites [76] source

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    Premisecitation

    CX516 produced no significant improvement in the primary outcome measure or in secondary measures of language, attention/executive function, or behavior compared with placebo, possibly due to the potency or dosage used.

    “No significant improvement in the primary outcome measure or in secondary measures of language, attention/executive function, or behavior was observed when compared with placebo, possibly due to the potency or dosage of CX516 used (105).”
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    • cites [105] source

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    Premisecitation

    In young mice, minocycline raises GluR1 phosphorylation and promotes subsequent AMPA receptor membrane insertion.

    “Treatment of young mice with minocycline, a broad-spectrum antibiotic, had a dual effect: increased phosphorylation of GluR1 and subsequent membrane insertion of AMPA receptors (124)”
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    • cites [124] source

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    Premisecitation

    Acamprosate blocks NMDA receptors and activates GABA A receptors; in three young adult patients with fragile X syndrome it produced global benefit and marked communication improvement.

    “Acamprosate, a molecule used to maintain abstinence from alcohol, is able to block NMDA-R as well as activate GABA A -R and was recently tested in three young adult patients with FXS, who showed global benefit (as rated by the CGI-I scale) and marked communication improvement (115).”
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    Premisecitation

    Treatment of Fmr1 knockout mice with the mGluR antagonist MPEP suppressed the audiogenic seizure phenotype and rescued dendritic spine morphology.

    “Treatment of Fmr1 KO mice with the mGluR antagonist 2-methyl-6-(phenylethynyl)-pyridine (MPEP) (Figure 3B) resulted in suppression of the audiogenic seizure phenotype (106) and rescue of dendritic spine morphology in the Fmr1 KO mouse (107).”
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    • cites [106] source

      Not checked in the free run.

    • cites [107] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In FXS mice, minocycline treatment improves anxiety and performance on a cognitive task.

    “and mice demonstrated improvements in anxiety and in a cognitive task (125).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [125] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Valproic acid is known as a reactivator of silenced genes and appeared to be a weak reactivator of full mutation.

    “The third tested compound is valproic acid (101), which is already known as a reactivator of silenced genes (102) that appeared to be a weak reactivator of FM (103).”
    Quote in the paperNot a substantial claim0 of 3 sources checked
    • cites [101] source

      Not checked in the free run.

    • cites [102] source

      Not checked in the free run.

    • cites [103] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Long-term use of the mGluR5 antagonist CTEC in adult animals corrected elevated hippocampal long-term depression, protein synthesis, spine dysmorphogenesis, overactive ERK and mTOR signaling, and partially corrected macroorchidism.

    “Long term use of a similar mGluR5 antagonist, CTEC, in adult animals corrected elevated hippocampal LTD, protein synthesis, spine dysmorphogenesis, overactive ERK and mTOR signaling, and partially corrected macroorchidism (108).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [108] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    Fenobam tested in adults with fragile X syndrome produced beneficial effects including reduced anxiety and hyperarousal, improved prepulse inhibition of startle, and better accuracy on a continuous performance task.

    “Fenobam, used in the past for anxiety treatment (109), was recently tested in adults with FXS (37).Beneficial effects such as reduced anxiety and hyperarousal, improved prepulse inhibition of startle, and better accuracy on a continuous performance task were also reported.”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [37] source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    In a small trial, AFQ056 improved inappropriate speech, stereotypic behavior, and hyperactivity in adults with fragile X syndrome who have a fully methylated full mutation allele but not in those with mosaicism.

    “Intriguingly, in this small trial, improvements in inappropriate speech, stereotypic behavior, and hyperactivity and efficacy have been reported in adults with FXS who have a fully methylated FM allele but not in those with mosaicism (36).”
    Quote in the paperNot a substantial claim0 of 1 sources checked
    • cites [36] Jacquemont, 2011, Sci Transl Med. source

      Not checked in the free run.

  • May combine two claims.

    Premisecitation

    FMRP is necessary for the proliferation, differentiation, and survival of neural stem and progenitor cells.

    “FMRP is also required for neural stem and progenitor cell proliferation, differentiation, and survival, suggesting additional mechanisms that could explain certain features of the disease (136).”
    Quote in the paperSubstantial claim0 of 1 sources checked
    • cites [136] source

      Not checked in the free run.

58 of 58

  • The paper relies on this without support.

    The Fmr1 knockout mouse model reproduces the morphological and behavioral features of human fragile X syndrome closely enough that molecular findings in it can guide targeted treatments for patients.

    “Because the mouse model recapitulates morphological changes and behavioral deficits seen in human patients, these molecular insights have led clinicians to design targeted treatments (see below).”

  • The paper relies on this without support.

    The FMR1 coding sequence remains intact in fragile X syndrome cells, so restoring gene activity is feasible.

    “The strategy of restoring FMR1 gene activity, which is based on the presence of the intact FMR1 coding sequence, targets potentially reversible epigenetic changes, primarily DNA methylation.”

  • The authors state this as an assumption.

    5-aza-deoxycytidine is effective only on dividing cells, so it would not act on postmitotic neurons.

    “Moreover, it is presumed to be effective only on dividing cells, which excludes postmitotic neurons.”

  • The paper relies on this without support.

    Modulating levels of dysregulated proteins can regulate impaired plasticity associated with FXS.

    “Another approach to regulate impaired plasticity associated with FXS is to modulate the levels of dysregulated proteins.”

  • The paper relies on this without support.

    FMRP functions in regulating mRNA metabolism in the brain.

    “FMRP is largely established to function in regulating mRNA metabolism in brain.”

  • The paper relies on this without support.

    Lack of FMRP causes dysregulated synthesis of synaptic molecules, including elevated levels of several proteins (Arc, αCAMKII, MMP9, GSK-3β, mGluR, NMDA) and reduced GABA and AMPA receptor activity.

    “Lack of FMRP leads to a dysregulated synthesis of molecules with key functions at synapses, such as increased levels of Arc, αCAMKII, MMP9, GSK-3β, mGluR, and NMDA and decreased GABA and AMPA receptor activity.”

  • The paper relies on this without support.

    The placebo effect observed in most drug-based trials is significant.

    “the significant placebo effect observed in most drug-based trials”
7 of 7

Claims other papers make about this one

Each is checked against this paper’s own text: does it say what the citing paper says it does?

  • Fragile X syndrome is due to loss of function of the RNA-binding protein FMRP.

    “FXS is due to loss of function of the RNA-binding protein FMRP (Bagni et al., 2012, Bassell and Warren, 2008), which regulates dendritic targeting of mRNAs (Dictenberg et al., 2008) and controls protein synthesis and mRNA decay in neuronal soma and at synapses (Bassell and Warren, 2008).”

    From CYFIP1 Coordinates mRNA Translation and Cytoskeleton Remodeling to Ensure Proper Dendritic Spine Formation (2013) · cites this paper as Bagni et al., 2012

  • Fragile X syndrome is caused by expansion of a CGG trinucleotide in the promoter of the FMR1 gene or, more rarely, by point mutations.

    “Fragile X syndrome is caused by expansion of a cytosine-guanine-guanine (CGG) trinucleotide in the promoter of the fragile X mental retardation (FMR1) gene or, more rarely, due to point mutations [18].”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [18]

  • Expansion of the CGG repeat over 200 copies leads to transcriptional silencing of the gene and loss of FMRP.

    “The expansion of the CGG repeat over 200 copies leads to the transcriptional silencing of the gene and loss of the fragile X mental retardation protein (FMRP).”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [18]

  • FMRP is an RNA-binding protein that interacts with specific mRNAs in the brain and regulates synaptic plasticity-dependent local protein synthesis.

    “FMRP is an RNA-binding protein known to interact with specific mRNAs in the brain and regulate synaptic plasticity-dependent local protein synthesis [18, 80, 275].”

    From Autism spectrum disorder: neuropathology and animal models (2017) · cites this paper as [18]

Self-check

Percentages, sums and reported differences re-computed from the paper’s own numbers.

Each contradiction between two passages listed here was confirmed by an independent check.

  • Normal and intermediate allele ranges overlap

    Minor

    The paper assigns 45-54 CGG repeats to both normal alleles and gray-zone or intermediate alleles, leaving their classification inconsistent.

1 of 1

Cites

Flagged first, then by citations

Research works printed but not linked: 6

  1. Fryns, 1984, Acta Paediatr Scand Suppl., 313, 1
  2. Tassone F, et al. Newborn screening in fragile X syndrome: prevalence and allele distribution of the FMR1 gene. Paper presented at: American College of Medical Genetics Annual Clinical Genetics Meeting; July 26, 2012; Charlotte, North Carolina, USA. http://www.fragilex.org/community/international-fragile-x-conference/miami2012/agenda/ . Accessed October 19, 2012.
  3. Hantash, 2010, MLO Med Lab Obs., 42, 20
  4. Meguid, 2012, Brain Cogn., 78, 74
  5. Bakker, 1994, Cell., 78, 23
  6. Gatto, 2010, Front Synaptic Neurosci., 2, 4

Cited by

Sorted by citations

Related

Authors
Bagni, C., Tassone, F., Neri, G., & Hagerman, R.
Affiliations
  • KU Leuven (BE)
  • University of California, Davis (US)
  • Università Cattolica del Sacro Cuore (IT)
Corresponding author
Bagni, Claudia
ORCID
Venue
Journal of Clinical Investigation
Publisher
American Society for Clinical Investigation
Published
2012-12-03
Volume
122
Issue
12
Pages
4314-4322
ISSN
0021-9738 (ISSN-L)
DOI
10.1172/jci63141
PMC
PMC3533539
OpenAlex
W2097267337
Semantic Scholar
d0bb26d811d90699694fe5287a4f71fdfc128aa8
Cited by
321
References
132
Citations by year
2026: 11 · 2025: 12 · 2024: 22 · 2023: 21 · 2022: 31 · 2021: 25 · 2020: 28 · 2019: 13 · 2018: 20 · 2017: 22 · 2016: 26 · 2015: 23 · 2014: 39 · 2013: 28
FWCI
17.07
Type
journal article
Language
en
Open access
Locations
  • Journal of Clinical Investigation (publishedVersion)
  • Europe PMC (PubMed Central) (publishedVersion)
  • PubMed Central (publishedVersion)
  • PubMed (publishedVersion)
  • Cineca Institutional Research Information System (Tor Vergata University) (submittedVersion, other-oa)
  • Lirias (submittedVersion, other-oa)
Funders
  • FRAXA Research Foundation
  • Compagnia di San Paolo
  • National Center for Research Resources (RR-024146, HD02274, HD036071, UL1RR024146)
  • Eunice Kennedy Shriver National Institute of Child Health and Human Development (HD036071, HD 02274, P30HD002274, R01HD036071)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Genetics › Genetics and Neurodevelopmental Disorders
  • Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
  • Health Sciences › Medicine › Public Health, Environmental and Occupational Health › Down syndrome and intellectual disability research
Keywords
fragile X syndrome, FMR1 gene, FMRP, trinucleotide repeat expansion, intellectual disability, mRNA metabolism, receptor signaling, behavioral interventions, pharmacological interventions, cognitive intervention, autism spectrum disorder
MeSH terms
Animals, Autistic Disorder, Fragile X Syndrome, Humans, Synaptic Transmission, Early Diagnosis, Epigenesis, Genetic, Fragile X Messenger Ribonucleoprotein 1, Molecular Targeted Therapy

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Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.

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