Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Fragile X syndrome

Abstract

Fragile X syndrome (FXS) is the leading inherited form of intellectual disability and autism spectrum disorder, and patients can present with severe behavioural alterations, including hyperactivity, impulsivity and anxiety, in addition to poor language development and seizures. FXS is a trinucleotide repeat disorder, in which >200 repeats of the CGG motif in FMR1 leads to silencing of the gene and the consequent loss of its product, fragile X mental retardation 1 protein (FMRP). FMRP has a central role in gene expression and regulates the translation of potentially hundreds of mRNAs, many of which are involved in the development and maintenance of neuronal synaptic connections. Indeed, disturbances in neuroplasticity is a key finding in FXS animal models, and an imbalance in inhibitory and excitatory neuronal circuits is believed to underlie many of the clinical manifestations of this disorder. Our knowledge of the proteins that are regulated by FMRP is rapidly growing, and this has led to the identification of multiple targets for therapeutic intervention, some of which have already moved into clinical trials or clinical practice.

Access options

Rent or Buy article

Get time limited or full article access on ReadCube.

from$8.99

All prices are NET prices.

Figure 1: Clinical features of FXS.
Figure 2: Physical features of FXS.
Figure 3: Glutamatergic signalling and DGKκ deregulation in FXS.
Figure 4: Altered GABAergic signalling in Fmr1-knockout mice.
Figure 5: The effect of FMRP loss on the BMPR–LIMK–cofilin pathway.
Figure 6: Caudate volume in individuals with fragile X syndrome.

References

  1. 1

    Myrick, L. K. et al. Fragile X syndrome due to a missense mutation. Eur. J. Hum. Genet. 22, 1185–1189 (2014).

    Google Scholar 

  2. 2

    Quartier, A. et al. Intragenic FMR1 disease-causing variants: a significant mutational mechanism leading to fragile-X syndrome. Eur. J. Hum. Genet. 25, 423–431 (2017). This paper provided an account of new intragenic mutations in FMR1 and an excellent review of the phenotypes associated with previously reported mutations in FMR1.

    Google Scholar 

  3. 3

    Hagerman, R. J. in Fragile X Syndrome: Diagnosis, Treatment and Research (eds Hagerman, R. J. & Hagerman, P. J. ) 3–109 (Johns Hopkins Univ. Press, 2002).

    Google Scholar 

  4. 4

    Berry-Kravis, E. et al. Seizures in fragile X syndrome: characteristics and comorbid diagnoses. Am. J. Intellect. Dev. Disabil. 115, 461–472 (2010).

    Google Scholar 

  5. 5

    Hogan, A. L. et al. Autism spectrum disorder symptoms in infants with fragile X syndrome: a prospective case series. J. Autism Dev. Disord. 47, 1628–1644 (2017).

    Google Scholar 

  6. 6

    Cordeiro, L., Ballinger, E., Hagerman, R. & Hessl, D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J. Neurodev. Disord. 3, 57–67 (2011).

    Google Scholar 

  7. 7

    Kidd, S. A. et al. Fragile X syndrome: a review of associated medical problems. Pediatrics 134, 995–1005 (2014). This was the first paper to compare frequency of medical problems in a large cohort with FXS with frequencies in the general paediatric population, defining those problems that are more common in FXS; it suggested medical screening and management of these problems for patients with FXS.

    Google Scholar 

  8. 8

    Heulens, I. et al. Craniofacial characteristics of fragile X syndrome in mouse and man. Eur. J. Hum. Genet. 21, 816–823 (2013).

    Google Scholar 

  9. 9

    Waldstein, G. et al. Fragile X syndrome: skin elastin abnormalities. Birth Defects Orig. Artic. Ser. 23, 103–114 (1987).

    Google Scholar 

  10. 10

    Pretto, D. et al. Clinical and molecular implications of mosaicism in FMR1 full mutations. Front. Genet. 5, 318 (2014).

    Google Scholar 

  11. 11

    Dyer-Friedman, J. et al. Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome. J. Am. Acad. Child Adolesc. Psychiatry 41, 237–244 (2002).

    Google Scholar 

  12. 12

    Loesch, D. Z., Huggins, R. M. & Hagerman, R. J. Phenotypic variation and FMRP levels in fragile X. Ment. Retard. Dev. Disabil. Res. Rev. 10, 31–41 (2004).

    Google Scholar 

  13. 13

    Oostra, B. A. & Hoogeveen, A. in Fragile X Syndrome: Diagnosis, Treatment and Research (eds Hagerman, R. J. & Hagerman, P. J. ) 169–190 (Johns Hopkins Univ. Press, 2002).

    Google Scholar 

  14. 14

    Tassone, F. et al. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am. J. Med. Genet. 84, 250–261 (1999).

    Google Scholar 

  15. 15

    Coffee, B. et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am. J. Hum. Genet. 85, 503–514 (2009).

    Google Scholar 

  16. 16

    Levesque, S. et al. Screening and instability of FMR1 alleles in a prospective sample of 24,449 mother-newborn pairs from the general population. Clin. Genet. 76, 511–523 (2009).

    Google Scholar 

  17. 17

    Fernandez-Carvajal, I. et al. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J. Mol. Diagn. 11, 324–329 (2009).

    Google Scholar 

  18. 18

    Song, F. J., Barton, P., Sleightholme, V., Yao, G. L. & Fry-Smith, A. Screening for fragile X syndrome: a literature review and modelling study. Health Technol. Assess. 7, 1–106 (2003).

    Google Scholar 

  19. 19

    Maia, N. et al. Contraction of fully expanded FMR1 alleles to the normal range: predisposing haplotype or rare events? J. Hum. Genet. 62, 269–275 (2017).

    Google Scholar 

  20. 20

    Hunter, J. et al. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am. J. Med. Genet. A 164A, 1648–1658 (2014). This was the largest meta-analysis study conducted to assess prevalence estimates of the full mutation and premutation in the total population.

    Google Scholar 

  21. 21

    Tassone, F. & Hall, D. A. FXTAS, FXPOI, and Other Premutation Disorders (Springer International Publishing, 2016). This comprehensive book discussed the clinical, epidemiological and molecular issues involved in the premutation disorders that can affect carriers of a premutation throughout their lifespan.

    Google Scholar 

  22. 22

    Khandjian, E. W., Corbin, F., Woerly, S. & Rousseau, F. The fragile X mental retardation protein is associated with ribosomes. Nat. Genet. 12, 91–93 (1996).

    Google Scholar 

  23. 23

    Tamanini, F. et al. FMRP is associated to the ribosomes via RNA. Hum. Mol. Genet. 5, 809–813 (1996).

    Google Scholar 

  24. 24

    Richter, J. D., Bassell, G. J. & Klann, E. Dysregulation and restoration of translational homeostasis in fragile X syndrome. Nat. Rev. Neurosci. 16, 595–605 (2015).

    Google Scholar 

  25. 25

    Darnell, J. C. & Klann, E. The translation of translational control by FMRP: therapeutic targets for FXS. Nat. Neurosci. 16, 1530–1536 (2013).

    Google Scholar 

  26. 26

    Brown, M. R. et al. Fragile X mental retardation protein controls gating of the sodium-activated potassium channel Slack. Nat. Neurosci. 13, 819–821 (2010).

    Google Scholar 

  27. 27

    Deng, P. Y. et al. FMRP regulates neurotransmitter release and synaptic information transmission by modulating action potential duration via BK channels. Neuron 77, 696–711 (2013).

    Google Scholar 

  28. 28

    Alpatov, R. et al. A chromatin-dependent role of the fragile X mental retardation protein FMRP in the DNA damage response. Cell 157, 869–881 (2014).

    Google Scholar 

  29. 29

    Shamay-Ramot, A. et al. Fmrp interacts with Adar and regulates RNA editing, synaptic density and locomotor activity in zebrafish. PLoS Genet. 11, e1005702 (2015).

    Google Scholar 

  30. 30

    Akins, M. R., Leblanc, H. F., Stackpole, E. E., Chyung, E. & Fallon, J. R. Systematic mapping of fragile X granules in the mouse brain reveals a potential role for presynaptic FMRP in sensorimotor functions. J. Comp. Neurol. 520, 3687–3706 (2012).

    Google Scholar 

  31. 31

    Guo, W. et al. Ablation of Fmrp in adult neural stem cells disrupts hippocampus-dependent learning. Nat. Med. 17, 559–565 (2011).

    Google Scholar 

  32. 32

    Nelson, D. L., Orr, H. T. & Warren, S. T. The unstable repeats — three evolving faces of neurological disease. Neuron 77, 825–843 (2013).

    Google Scholar 

  33. 33

    Vershkov, D. & Benvenisty, N. Human pluripotent stem cells in modeling human disorders: the case of fragile X syndrome. Regen. Med. 12, 53–68 (2017).

    Google Scholar 

  34. 34

    Colak, D. et al. Promoter-bound trinucleotide repeat mRNA drives epigenetic silencing in fragile X syndrome. Science 343, 1002–1005 (2014).

    Google Scholar 

  35. 35

    Gerhardt, J. et al. The DNA replication program is altered at the FMR1 locus in fragile X embryonic stem cells. Mol. Cell 53, 19–31 (2014).

    Google Scholar 

  36. 36

    Mirkin, S. M. Expandable DNA repeats and human disease. Nature 447, 932–940 (2007).

    Google Scholar 

  37. 37

    Zhao, X. N. et al. Mutsβ generates both expansions and contractions in a mouse model of the fragile X-associated disorders. Hum. Mol. Genet. 24, 7087–7096 (2015).

    Google Scholar 

  38. 38

    Gholizadeh, S., Halder, S. K. & Hampson, D. R. Expression of fragile X mental retardation protein in neurons and glia of the developing and adult mouse brain. Brain Res. 1596, 22–30 (2015).

    Google Scholar 

  39. 39

    Bakker, C. E. & Oostra, B. A. Understanding fragile X syndrome: insights from animal models. Cytogenet. Genome Res. 100, 111–123 (2003).

    Google Scholar 

  40. 40

    The Dutch-Belgian Fragile X Consortium. Fmr1 knockout mice: a model to study fragile X mental retardation. Cell 78, 23–33 (1994).

    Google Scholar 

  41. 41

    Kooy, R. F. Of mice and the fragile X syndrome. Trends Genet. 19, 148–154 (2003).

    Google Scholar 

  42. 42

    Huber, K. M., Gallagher, S. M., Warren, S. T. & Bear, M. F. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc. Natl Acad. Sci. USA 99, 7746–7750 (2002). This paper established that loss of FMRP causes exaggerated protein synthesis-dependent mGluRI signalling in the Fmr1-knockout mouse model.

    Google Scholar 

  43. 43

    Kaufmann, W. E. et al. Autism spectrum disorder in fragile X syndrome: cooccurring conditions and current treatment. Pediatrics 139, S194–S206 (2017).

    Google Scholar 

  44. 44

    Li, J., Pelletier, M. R., Perez Velazquez, J. L. & Carlen, P. L. Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol. Cell. Neurosci. 19, 138–151 (2002).

    Google Scholar 

  45. 45

    Sidorov, M. S., Auerbach, B. D. & Bear, M. F. Fragile X mental retardation protein and synaptic plasticity. Mol. Brain 6, 15 (2013).

    Google Scholar 

  46. 46

    Qin, M., Kang, J., Burlin, T. V., Jiang, C. & Smith, C. B. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouse. J. Neurosci. 25, 5087–5095 (2005).

    Google Scholar 

  47. 47

    Dolen, G. et al. Correction of fragile X syndrome in mice. Neuron 56, 955–962 (2007).

    Google Scholar 

  48. 48

    Contractor, A., Klyachko, V. A. & Portera-Cailliau, C. Altered neuronal and circuit excitability in fragile X syndrome. Neuron 87, 699–715 (2015).

    Google Scholar 

  49. 49

    Miller, L. J. et al. Electrodermal responses to sensory stimuli in individuals with fragile X syndrome: a preliminary report. Am. J. Med. Genet. 83, 268–279 (1999).

    Google Scholar 

  50. 50

    Santoro, M. R., Bray, S. M. & Warren, S. T. Molecular mechanisms of fragile X syndrome: a twenty-year perspective. Annu. Rev. Pathol. 7, 219–245 (2012).

    Google Scholar 

  51. 51

    Braat, S. & Kooy, R. F. Fragile X syndrome neurobiology translates into rational therapy. Drug Discov. Today 19, 510–519 (2014).

    Google Scholar 

  52. 52

    Pop, A. S., Gomez-Mancilla, B., Neri, G., Willemsen, R. & Gasparini, F. Fragile X syndrome: a preclinical review on metabotropic glutamate receptor 5 (mGluR5) antagonists and drug development. Psychopharmacology (Berl.) 231, 1217–1226 (2014).

    Google Scholar 

  53. 53

    Bear, M. F., Huber, K. M. & Warren, S. T. The mGluR theory of fragile X mental retardation. Trends Neurosci. 27, 370–377 (2004).

    Google Scholar 

  54. 54

    Pfeiffer, B. E. & Huber, K. M. Current advances in local protein synthesis and synaptic plasticity. J. Neurosci. 26, 7147–7150 (2006).

    Google Scholar 

  55. 55

    Sutton, M. A. & Schuman, E. M. Dendritic protein synthesis, synaptic plasticity, and memory. Cell 127, 49–58 (2006).

    Google Scholar 

  56. 56

    Gkogkas, C. G. et al. Pharmacogenetic inhibition of eIF4E-dependent Mmp9 mRNA translation reverses fragile X syndrome-like phenotypes. Cell Rep. 9, 1742–1755 (2014).

    Google Scholar 

  57. 57

    Sawicka, K., Pyronneau, A., Chao, M., Bennett, M. V. & Zukin, R. S. Elevated ERK/p90 ribosomal S6 kinase activity underlies audiogenic seizure susceptibility in fragile X mice. Proc. Natl Acad. Sci. USA 113, E6290–E6297 (2016).

    Google Scholar 

  58. 58

    Hoeffer, C. A. et al. Altered mTOR signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 11, 332–341 (2012).

    Google Scholar 

  59. 59

    Braat, S. & Kooy, R. F. Insights into GABAAergic system deficits in fragile X syndrome lead to clinical trials. Neuropharmacology 88, 48–54 (2015).

    Google Scholar 

  60. 60

    Gross, C. et al. Increased expression of the PI3K enhancer PIKE mediates deficits in synaptic plasticity and behavior in fragile X syndrome. Cell Rep. 11, 727–736 (2015).

    Google Scholar 

  61. 61

    Sidhu, H., Dansie, L. E., Hickmott, P. W., Ethell, D. W. & Ethell, I. M. Genetic removal of matrix metalloproteinase 9 rescues the symptoms of fragile X syndrome in a mouse model. J. Neurosci. 34, 9867–9879 (2014).

    Google Scholar 

  62. 62

    Guo, W. et al. Inhibition of GSK3β improves hippocampus-dependent learning and rescues neurogenesis in a mouse model of fragile X syndrome. Hum. Mol. Genet. 21, 681–691 (2012).

    Google Scholar 

  63. 63

    Pasciuto, E. et al. Dysregulated ADAM10-mediated processing of APP during a critical time window leads to synaptic deficits in fragile X syndrome. Neuron 87, 382–398 (2015).

    Google Scholar 

  64. 64

    Westmark, C. J. et al. Reversal of fragile X phenotypes by manipulation of AβPP/Aβ levels in Fmr1KO mice. PLoS ONE 6, e26549 (2011).

    Google Scholar 

  65. 65

    Tabet, R. et al. Fragile X mental retardation protein (FMRP) controls diacylglycerol kinase activity in neurons. Proc. Natl Acad. Sci. USA 113, E3619–E3628 (2016). This paper identified the dysregulation of the DAG/PA homeostasis in neurons lacking FMRP as the possible molecular cause of mGluR signalling alteration.

    Google Scholar 

  66. 66

    Michaluk, P. et al. Influence of matrix metalloproteinase MMP-9 on dendritic spine morphology. J. Cell Sci. 124, 3369–3380 (2011).

    Google Scholar 

  67. 67

    Dziembowska, M. et al. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am. J. Med Genet. A 161A, 1897–1903 (2013).

    Google Scholar 

  68. 68

    Bilousova, T. V. et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J. Med. Genet. 46, 94–102 (2009).

    Google Scholar 

  69. 69

    Rotschafer, S. E., Trujillo, M. S., Dansie, L. E., Ethell, I. M. & Razak, K. A. Minocycline treatment reverses ultrasonic vocalization production deficit in a mouse model of fragile X syndrome. Brain Res. 1439, 7–14 (2012).

    Google Scholar 

  70. 70

    Gantois, I. et al. Metformin ameliorates core deficits in a mouse model of fragile X syndrome. 23, 674–677 (2017).

  71. 71

    Imai, S., Kai, M., Yasuda, S., Kanoh, H. & Sakane, F. Identification and characterization of a novel human type II diacylglycerol kinase, DGKκ. J. Biol. Chem. 280, 39870–39881 (2005).

    Google Scholar 

  72. 72

    Sakane, F., Imai, S., Kai, M., Yasuda, S. & Kanoh, H. Diacylglycerol kinases as emerging potential drug targets for a variety of diseases. Curr. Drug Targets 9, 626–640 (2008).

    Google Scholar 

  73. 73

    van der Zanden, L. F. et al. Common variants in DGKK are strongly associated with risk of hypospadias. Nat. Genet. 43, 48–50 (2011).

    Google Scholar 

  74. 74

    Kim, K., Yang, J. & Kim, E. Diacylglycerol kinases in the regulation of dendritic spines. J. Neurochem. 112, 577–587 (2010).

    Google Scholar 

  75. 75

    Hall, S. S., Lightbody, A. A., Hirt, M., Rezvani, A. & Reiss, A. L. Autism in fragile X syndrome: a category mistake? J. Am. Acad. Child Adolesc. Psychiatry 49, 921–933 (2010).

    Google Scholar 

  76. 76

    Mouslech, Z. & Valla, V. Endocannabinoid system: an overview of its potential in current medical practice. Neuro Endocrinol. Lett. 30, 153–179 (2009).

    Google Scholar 

  77. 77

    Pacher, P., Batkai, S. & Kunos, G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol. Rev. 58, 389–462 (2006).

    Google Scholar 

  78. 78

    Zhang, L. & Alger, B. E. Enhanced endocannabinoid signaling elevates neuronal excitability in fragile X syndrome. J. Neurosci. 30, 5724–5729 (2010).

    Google Scholar 

  79. 79

    Maccarrone, M. et al. Abnormal mGlu 5 receptor/endocannabinoid coupling in mice lacking FMRP and BC1 RNA. Neuropsychopharmacology 35, 1500–1509 (2010).

    Google Scholar 

  80. 80

    Busquets-Garcia, A. et al. Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat. Med. 19, 603–607 (2013).

    Google Scholar 

  81. 81

    Jung, K. M. et al. Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat. Commun. 3, 1080 (2012).

    Google Scholar 

  82. 82

    Myrick, L. K. et al. Independent role for presynaptic FMRP revealed by an FMR1 missense mutation associated with intellectual disability and seizures. Proc. Natl Acad. Sci. USA 112, 949–956 (2015).

    Google Scholar 

  83. 83

    Ferron, L., Nieto-Rostro, M., Cassidy, J. S. & Dolphin, A. C. Fragile X mental retardation protein controls synaptic vesicle exocytosis by modulating N-type calcium channel density. Nat. Commun. 5, 3628 (2014).

    Google Scholar 

  84. 84

    Darnell, J. C. et al. Fragile X mental retardation protein targets G quartet mRNAs important for neuronal function. Cell 107, 489–499 (2001).

    Google Scholar 

  85. 85

    Brown, V. et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell 107, 477–487 (2001).

    Google Scholar 

  86. 86

    Suhl, J. A., Chopra, P., Anderson, B. R., Bassell, G. J. & Warren, S. T. Analysis of FMRP mRNA target datasets reveals highly associated mRNAs mediated by G-quadruplex structures formed via clustered WGGA sequences. Hum. Mol. Genet. 23, 5479–5491 (2014).

    Google Scholar 

  87. 87

    Braat, S. & Kooy, R. F. The GABAA receptor as a therapeutic target for neurodevelopmental disorders. Neuron 86, 1119–1130 (2015). This paper highlighted that the GABAergic system is compromised in a range of related neurodevelopmental disorders, including FXS.

    Google Scholar 

  88. 88

    Curia, G., Papouin, T., Seguela, P. & Avoli, M. Downregulation of tonic GABAergic inhibition in a mouse model of fragile X syndrome. Cereb. Cortex 19, 1515–1520 (2009).

    Google Scholar 

  89. 89

    Sabanov, V. et al. Impaired GABAergic inhibition in the hippocampus of Fmr1 knockout mice. Neuropharmacology 116, 71–81 (2017).

    Google Scholar 

  90. 90

    Olmos-Serrano, J. L. et al. Defective GABAergic neurotransmission and pharmacological rescue of neuronal hyperexcitability in the amygdala in a mouse model of fragile X syndrome. J. Neurosci. 30, 9929–9938 (2010).

    Google Scholar 

  91. 91

    Vislay, R. L. et al. Homeostatic responses fail to correct defective amygdala inhibitory circuit maturation in fragile X syndrome. J. Neurosci. 33, 7548–7558 (2013).

    Google Scholar 

  92. 92

    Centonze, D. et al. Abnormal striatal GABA transmission in the mouse model for the fragile X syndrome. Biol. Psychiatry 63, 963–973 (2008).

    Google Scholar 

  93. 93

    Paluszkiewicz, S. M., Olmos-Serrano, J. L., Corbin, J. G. & Huntsman, M. M. Impaired inhibitory control of cortical synchronization in fragile X syndrome. J. Neurophysiol. 106, 2264–2272 (2011).

    Google Scholar 

  94. 94

    Gibson, J. R., Bartley, A. F., Hays, S. A. & Huber, K. M. Imbalance of neocortical excitation and inhibition and altered UP states reflect network hyperexcitability in the mouse model of fragile X syndrome. J. Neurophysiol. 100, 2615–2626 (2008).

    Google Scholar 

  95. 95

    He, Q., Nomura, T., Xu, J. & Contractor, A. The developmental switch in GABA polarity is delayed in fragile X mice. J. Neurosci. 34, 446–450 (2014).

    Google Scholar 

  96. 96

    Tyzio, R. et al. Oxytocin-mediated GABA inhibition during delivery attenuates autism pathogenesis in rodent offspring. Science 343, 675–679 (2014).

    Google Scholar 

  97. 97

    D’Hulst, C. & Kooy, R. F. The GABAA receptor: a novel target for treatment of fragile X? Trends Neurosci. 30, 425–431 (2007).

    Google Scholar 

  98. 98

    Lozano, R., Hare, E. B. & Hagerman, R. J. Modulation of the GABAergic pathway for the treatment of fragile X syndrome. Neuropsychiatr. Dis. Treat. 10, 1769–1779 (2014).

    Google Scholar 

  99. 99

    Chang, S. et al. Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat. Chem. Biol. 4, 256–263 (2008).

    Google Scholar 

  100. 100

    Olmos-Serrano, J. L., Corbin, J. G. & Burns, M. P. The GABAA receptor agonist THIP ameliorates specific behavioral deficits in the mouse model of fragile X syndrome. Dev. Neurosci. 33, 395–403 (2011).

    Google Scholar 

  101. 101

    Reddy, D. S. & Estes, W. A. Clinical potential of neurosteroids for CNS disorders. Trends Pharmacol. Sci. 37, 543–561 (2016).

    Google Scholar 

  102. 102

    Tassone, F. Advanced technologies for the molecular diagnosis of fragile X syndrome. Expert Rev. Mol. Diagn. 15, 1465–1473 (2015).

    Google Scholar 

  103. 103

    Braat, S. et al. The GABAA receptor is an FMRP target with therapeutic potential in fragile X syndrome. Cell Cycle 14, 2985–2995 (2015).

    Google Scholar 

  104. 104

    Kashima, R. et al. Augmented noncanonical BMP type II receptor signaling mediates the synaptic abnormality of fragile X syndrome. Sci. Signal. 9, ra58 (2016).

    Google Scholar 

  105. 105

    Hagerman, P. Fragile X-associated tremor/ataxia syndrome (FXTAS): pathology and mechanisms. Acta Neuropathol. 126, 1–19 (2013).

    Google Scholar 

  106. 106

    Hazlett, H. C. et al. Trajectories of early brain volume development in fragile X syndrome and autism. J. Am. Acad. Child Adolesc. Psychiatry 51, 921–933 (2012).

    Google Scholar 

  107. 107

    Reiss, A. L., Abrams, M. T., Greenlaw, R., Freund, L. & Denckla, M. B. Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat. Med. 1, 159–167 (1995).

    Google Scholar 

  108. 108

    Reiss, A. L., Patel, S., Kumar, A. J. & Freund, L. Preliminary communication: neuroanatomical variations of the posterior fossa in men with the fragile X (Martin–Bell) syndrome. Am. J. Med. Genet. 31, 407–414 (1988).

    Google Scholar 

  109. 109

    Mostofsky, S. H. et al. Decreased cerebellar posterior vermis size in fragile X syndrome: correlation with neurocognitive performance. Neurology 50, 121–130 (1998).

    Google Scholar 

  110. 110

    Gothelf, D. et al. Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP). Ann. Neurol. 63, 40–51 (2008).

    Google Scholar 

  111. 111

    Hoeft, F. et al. Morphometric spatial patterns differentiating boys with fragile X syndrome, typically developing boys, and developmentally delayed boys aged 1 to 3 years. Arch. Gen. Psychiatry 65, 1087–1097 (2008).

    Google Scholar 

  112. 112

    Wang, J. Y. et al. Abnormal trajectories in cerebellum and brainstem volumes in carriers of the fragile X premutation. Neurobiol. Aging 55, 11–19 (2017).

    Google Scholar 

  113. 113

    Shelton, A. L. et al. White matter microstructure, cognition, and molecular markers in fragile X premutation females. Neurology 88, 2080–2088 (2017).

    Google Scholar 

  114. 114

    Eliez, S., Blasey, C. M., Freund, L. S., Hastie, T. & Reiss, A. L. Brain anatomy, gender and IQ in children and adolescents with fragile X syndrome. Brain 124, 1610–1618 (2001).

    Google Scholar 

  115. 115

    Hazlett, H. C. et al. Teasing apart the heterogeneity of autism: same behavior, different brains in toddlers with fragile X syndrome and autism. J. Neurodev. Disord. 1, 81–90 (2009).

    Google Scholar 

  116. 116

    Bruno, J. L. et al. Altered brain network segregation in fragile X syndrome revealed by structural connectomics. Cereb. Cortex 27, 2249–2259 (2017).

    Google Scholar 

  117. 117

    Bruno, J. L. et al. Aberrant basal ganglia metabolism in fragile X syndrome: a magnetic resonance spectroscopy study. J. Neurodev. Disord. 5, 20 (2013).

    Google Scholar 

  118. 118

    Wolff, J. J., Hazlett, H. C., Lightbody, A. A., Reiss, A. L. & Piven, J. Repetitive and self-injurious behaviors: associations with caudate volume in autism and fragile X syndrome. J. Neurodev. Disord. 5, 12 (2013).

    Google Scholar 

  119. 119

    Reiss, A. L., Lee, J. & Freund, L. Neuroanatomy of fragile X syndrome: the temporal lobe. Neurology 44, 1317–1324 (1994).

    Google Scholar 

  120. 120

    Kates, W. R., Abrams, M. T., Kaufmann, W. E., Breiter, S. N. & Reiss, A. L. Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiatry Res. 75, 31–48 (1997).

    Google Scholar 

  121. 121

    Jakala, P. et al. Fragile-X: neuropsychological test performance, CGG triplet repeat lengths, and hippocampal volumes. J. Clin. Invest. 100, 331–338 (1997).

    Google Scholar 

  122. 122

    Hall, S. S., Dougherty, R. F. & Reiss, A. L. Profiles of aberrant white matter microstructure in fragile X syndrome. Neuroimage Clin. 11, 133–138 (2016).

    Google Scholar 

  123. 123

    Hall, S. S., Jiang, H., Reiss, A. L. & Greicius, M. D. Identifying large-scale brain networks in fragile X syndrome. JAMA Psychiatry 70, 1215–1223 (2013).

    Google Scholar 

  124. 124

    Garrett, A. S., Menon, V., MacKenzie, K. & Reiss, A. L. Here's looking at you, kid: neural systems underlying face and gaze processing in fragile X syndrome. Arch. Gen. Psychiatry 61, 281–288 (2004).

    Google Scholar 

  125. 125

    Watson, C., Hoeft, F., Garrett, A. S., Hall, S. S. & Reiss, A. L. Aberrant brain activation during gaze processing in boys with fragile X syndrome. Arch. Gen. Psychiatry 65, 1315–1323 (2008).

    Google Scholar 

  126. 126

    Holsen, L. M., Dalton, K. M., Johnstone, T. & Davidson, R. J. Prefrontal social cognition network dysfunction underlying face encoding and social anxiety in fragile X syndrome. Neuroimage 43, 592–604 (2008).

    Google Scholar 

  127. 127

    Kwon, H. et al. Functional neuroanatomy of visuospatial working memory in fragile X syndrome: relation to behavioral and molecular measures. Am. J. Psychiatry 158, 1040–1051 (2001).

    Google Scholar 

  128. 128

    Menon, V., Leroux, J., White, C. D. & Reiss, A. L. Frontostriatal deficits in fragile X syndrome: relation to FMR1 gene expression. Proc. Natl Acad. Sci. USA 101, 3615–3620 (2004).

    Google Scholar 

  129. 129

    Rivera, S. M., Menon, V., White, C. D., Glaser, B. & Reiss, A. L. Functional brain activation during arithmetic processing in females with fragile X syndrome is related to FMR1 protein expression. Hum. Brain Mapp. 16, 206–218 (2002).

    Google Scholar 

  130. 130

    Klabunde, M. et al. Examining the neural correlates of emergent equivalence relations in fragile X syndrome. Psychiatry Res. 233, 373–379 (2015).

    Google Scholar 

  131. 131

    Tamm, L., Menon, V., Johnston, C. K., Hessl, D. R. & Reiss, A. L. fMRI study of cognitive interference processing in females with fragile X syndrome. J. Cogn. Neurosci. 14, 160–171 (2002).

    Google Scholar 

  132. 132

    Hoeft, F. et al. Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndrome. Hum. Brain Mapp. 28, 543–554 (2007).

    Google Scholar 

  133. 133

    Rajan-Babu, I. S. & Chong, S. S. Molecular correlates and recent advancements in the diagnosis and screening of FMR1-related disorders. Genes 7 E87 (2016).

    Google Scholar 

  134. 134

    Yrigollen, C. M. et al. AGG interruptions within the maternal FMR1 gene reduce the risk of offspring with fragile X syndrome. Genet. Med. 14, 729–736 (2012).

    Google Scholar 

  135. 135

    Nolin, S. L. et al. Fragile X AGG analysis provides new risk predictions for 45–69 repeat alleles. Am. J. Med Genet. A 161A, 771–778 (2013).

    Google Scholar 

  136. 136

    Yrigollen, C. M. et al. AGG interruptions and maternal age affect FMR1 CGG repeat allele stability during transmission. J. Neurodev. Disord. 6, 24 (2014). This large study aimed to determine the predicted risk to expansion to a full mutation during maternal transmission, and it identified CGG repeat number, AGG interruptions and maternal age as the main players.

    Google Scholar 

  137. 137

    Bailey, D. B. Jr, Raspa, M., Bishop, E. & Holiday, D. No change in the age of diagnosis for fragile X syndrome: findings from a national parent survey. Pediatrics 124, 527–533 (2009).

    Google Scholar 

  138. 138

    Tassone, F. et al. FMR1 CGG allele size and prevalence ascertained through newborn screening in the United States. Genome Med. 4, 100 (2012).

    Google Scholar 

  139. 139

    Harris, S. W. et al. Autism profiles of males with fragile X syndrome. Am. J. Ment. Retard. 113, 427–438 (2008).

    Google Scholar 

  140. 140

    Kaufmann, W. E. et al. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am. J. Med Genet. A 129A, 225–234 (2004).

    Google Scholar 

  141. 141

    Yuhas, J. et al. High-risk fragile X screening in Guatemala: use of a new blood spot polymerase chain reaction technique. Genet. Test. Mol. Biomarkers 13, 855–859 (2009).

    Google Scholar 

  142. 142

    Winarni, T. I. et al. Identification of expanded alleles of the FMR1 gene among high-risk population in Indonesia by using blood spot screening. Genet. Test. Mol. Biomarkers 16, 162–166 (2012).

    Google Scholar 

  143. 143

    Kanwal, M. et al. Molecular diagnosis of fragile X syndrome in subjects with intellectual disability of unknown origin: implications of its prevalence in regional Pakistan. PLoS ONE 10, e0122213 (2015).

    Google Scholar 

  144. 144

    McConkie-Rosell, A. et al. Recommendations from multi-disciplinary focus groups on cascade testing and genetic counseling for fragile X-associated disorders. J. Genet. Couns. 16, 593–606 (2007).

    Google Scholar 

  145. 145

    Berman, R. F. et al. Mouse models of the fragile X premutation and fragile X-associated tremor/ataxia syndrome. J. Neurodev. Disord. 6, 25 (2014).

    Google Scholar 

  146. 146

    Polussa, J., Schneider, A. & Hagerman, R. Molecular advances leading to treatment implications for fragile X premutation carriers. Brain Disord. Ther. 3 1000119 (2014).

    Google Scholar 

  147. 147

    Visootsak, J. et al. Climbing the branches of a family tree: diagnosis of fragile X syndrome. J. Pediatr. 164, 1292–1295 (2014).

    Google Scholar 

  148. 148

    Rogers, S. J. et al. Teaching young nonverbal children with autism useful speech: a pilot study of the Denver Model and PROMPT interventions. J. Autism Dev. Disord. 36, 1007–1024 (2006).

    Google Scholar 

  149. 149

    Dawson, G. et al. Randomized, controlled trial of an intervention for toddlers with autism: the Early Start Denver Model. Pediatrics 125, e17–23 (2010).

    Google Scholar 

  150. 150

    Dawson, G. et al. Early behavioral intervention is associated with normalized brain activity in young children with autism. J. Am. Acad. Child Adolesc. Psychiatry 51, 1150–1159 (2012).

    Google Scholar 

  151. 151

    Braden, M. L. Fragile, Handle with Care: More About Fragile X Syndrome, Adolescents and Adults (Spectra Publishing Co., 2000).

    Google Scholar 

  152. 152

    Hills Epstein, J. L., Riley, K. & Sobesky, W. in Fragile X Syndrome: Diagnosis, Treatment, and Research (eds Hagerman, R. J. & Hagerman, P. J. ) 339–362 (Johns Hopkins Univ. Press, 2002).

    Google Scholar 

  153. 153

    Hagerman, R. J., Murphy, M. A. & Wittenberger, M. D. A controlled trial of stimulant medication in children with the fragile X syndrome. Am. J. Med. Genet. 30, 377–392 (1988).

    Google Scholar 

  154. 154

    Hagerman, R. J. et al. Advances in the treatment of fragile X syndrome. Pediatrics 123, 378–390 (2009).

    Google Scholar 

  155. 155

    Wirojanan, J. et al. The efficacy of melatonin for sleep problems in children with autism, fragile X syndrome, or autism and fragile X syndrome. J. Clin. Sleep Med. 5, 145–150 (2009).

    Google Scholar 

  156. 156

    Torrioli, M. G. et al. Double-blind, placebo-controlled study of L-acetylcarnitine for the treatment of hyperactive behavior in fragile X syndrome. Am. J. Med. Genet. 87, 366–368 (1999).

    Google Scholar 

  157. 157

    Torrioli, M. et al. Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys. Am. J. Med Genet. A 152A, 1420–1427 (2010).

    Google Scholar 

  158. 158

    Greiss Hess, L. et al. A randomized, double-blind, placebo-controlled trial of low-dose sertraline in young children with fragile X syndrome. J. Dev. Behav. Pediatr. 37, 619–628 (2016). This paper used a low dose of sertraline in young children (2–6 years of age) with FXS and found significant improvement compared with placebo in development, including visual reception, fine motor coordination, composite cognitive score and, in those with FXS plus ASD, overall expressive language score. This work suggested that early treatment with low-dose sertraline is beneficial and can be used clinically.

    Google Scholar 

  159. 159

    Erickson, C. A., Stigler, K. A., Posey, D. J. & McDougle, C. J. Aripiprazole in autism spectrum disorders and fragile X syndrome. Neurotherapeutics 7, 258–263 (2010).

    Google Scholar 

  160. 160

    Hersh, J. H. & Saul, R. A. Health supervision for children with fragile X syndrome. Pediatrics 127, 994–1006 (2011).

    Google Scholar 

  161. 161

    Kronk, R. et al. Prevalence, nature, and correlates of sleep problems among children with fragile X syndrome based on a large scale parent survey. Sleep 33, 679–687 (2010).

    Google Scholar 

  162. 162

    McLennan, Y., Polussa, J., Tassone, F. & Hagerman, R. Fragile X syndrome. Curr. Genomics 12, 216–224 (2011).

    Google Scholar 

  163. 163

    Nowicki, S. T. et al. The Prader–Willi phenotype of fragile X syndrome. J. Dev. Behav. Pediatr. 28, 133–138 (2007).

    Google Scholar 

  164. 164

    Dy, A. B. C. et al. Metformin as targeted treatment in fragile X syndrome. Clin. Genet.http://dx.doi.org/10.1111/cge.13039 (2017).

  165. 165

    Berry-Kravis, E. et al. Mavoglurant in fragile X syndrome: results of two randomized, double-blind, placebo-controlled trials. Sci. Transl Med. 8, 321ra325 (2016). This was hitherto the largest phase IIb clinical trial and illustrated the complexity of FXS pathology and the difficulty of the translation of human treatments validated in mouse models.

    Google Scholar 

  166. 166

    Jacquemont, S. et al. Epigenetic modification of the FMR1 gene in fragile X. syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci. Transl Med. 3, 64ra61 (2011).

    Google Scholar 

  167. 167

    Wang, H. et al. FMRP acts as a key messenger for dopamine modulation in the forebrain. Neuron 59, 634–647 (2008).

    Google Scholar 

  168. 168

    Curie, A. et al. Placebo responses in genetically determined intellectual disability: a meta-analysis. PLoS ONE 10, e0133316 (2015).

    Google Scholar 

  169. 169

    Budimirovic, D. B. et al. Updated report on tools to measure outcomes of clinical trials in fragile X syndrome. J. Neurodev. Disord. 9, 14 (2017).

    Google Scholar 

  170. 170

    Henderson, C. et al. Reversal of disease-related pathologies in the fragile X mouse model by selective activation of GABAB receptors with arbaclofen. Sci. Transl Med. 4, 152ra128 (2012).

    Google Scholar 

  171. 171

    Berry-Kravis, E. M. et al. Effects of STX209 (arbaclofen) on neurobehavioral function in children and adults with fragile X syndrome: a randomized, controlled, phase 2 trial. Sci. Transl Med. 4, 152ra127 (2012).

    Google Scholar 

  172. 172

    Sansone, S. M. et al. Psychometric study of the Aberrant Behavior Checklist in fragile X syndrome and implications for targeted treatment. J. Autism Dev. Disord. 42, 1377–1392 (2012).

    Google Scholar 

  173. 173

    Berry-Kravis, E. et al. Arbaclofen in fragile X syndrome: results of phase 3 trials. J. Neurodev. Disord. 9, 3 (2017).

    Google Scholar 

  174. 174

    Erickson, C. A. et al. Impact of acamprosate on behavior and brain-derived neurotrophic factor: an open-label study in youth with fragile X syndrome. Psychopharmacology (Berl.) 228, 75–84 (2013).

    Google Scholar 

  175. 175

    Erickson, C. A. et al. Impact of acamprosate on plasma amyloid-beta precursor protein in youth: a pilot analysis in fragile X syndrome-associated and idiopathic autism spectrum disorder suggests a pharmacodynamic protein marker. J. Psychiatr. Res. 59, 220–228 (2014).

    Google Scholar 

  176. 176

    Berry-Kravis, E., Rubin, J., Harary, E. & Daniely, Y. A 6-week, randomized, multicenter, double-blind, parallel, flexed- and fixed-dose study of MDX (metadoxine extended-release; MG01CI) compared with placebo in adolescents and adults with fragile X syndrome. AACAPhttp://files.shareholder.com/downloads/AMDA-1SVKDP/0x0x858015/E85D78F1-33D2-46F4-B4C7-96472D1F9A22/AACAP_AL014_poster_final.pdf (2015).

  177. 177

    Knox, A. et al. Feasibility, reliability, and clinical validity of the Test of Attentional Performance for Children (KiTAP) in fragile X syndrome (FXS). J. Neurodev. Disord. 4, 2 (2012).

    Google Scholar 

  178. 178

    Ligsay, A. et al. A randomized double-blind, placebo-controlled trial of ganaxolone in children and adolescents with fragile X syndrome. J. Neurodev. Disord. 9, 26 (2017).

    Google Scholar 

  179. 179

    McDuffie, A. et al. Distance video-teleconferencing in early intervention. Top. Early Childhood Special Educ. 33, 172–185 (2013).

    Google Scholar 

  180. 180

    McDuffie, A. et al. A spoken-language intervention for school-aged boys with fragile X syndrome. Am. J. Intellect. Dev. Disabil. 121, 236–265 (2016).

    Google Scholar 

  181. 181

    McDuffie, A. et al. Early language intervention using distance video-teleconferencing: a pilot study of young boys with fragile X syndrome and their mothers. Am. J. Speech Lang. Pathol. 25, 46–66 (2016).

    Google Scholar 

  182. 182

    Schneider, A. et al. Electrocortical changes associated with minocycline treatment in fragile X syndrome. J. Psychopharmacol. 27, 956–963 (2013).

    Google Scholar 

  183. 183

    Farzin, F., Scaggs, F., Hervey, C., Berry-Kravis, E. & Hessl, D. Reliability of eye tracking and pupillometry measures in individuals with fragile X syndrome. J. Autism Dev. Disord. 41, 1515–1522 (2011).

    Google Scholar 

  184. 184

    Berry-Kravis, E. et al. Sensitivity of the KiTAP executive function battery and an eye tracking paradigm to effects of AFQ056 in fragile X syndrome. Ann. Neurol. 80, S413 (2016).

    Google Scholar 

  185. 185

    Paribello, C. et al. Open-label add-on treatment trial of minocycline in fragile X syndrome. BMC Neurol. 10, 91 (2010).

    Google Scholar 

  186. 186

    Utari, A. et al. Side effects of minocycline treatment in patients with fragile X syndrome and exploration of outcome measures. Am. J. Intellect. Dev. Disabil. 115, 433–443 (2010).

    Google Scholar 

  187. 187

    Leigh, M. J. et al. A randomized double-blind, placebo-controlled trial of minocycline in children and adolescents with fragile x syndrome. J. Dev. Behav. Pediatr. 34, 147–155 (2013).

    Google Scholar 

  188. 188

    Monyak, R. E. et al. Insulin signaling misregulation underlies circadian and cognitive deficits in a Drosophila fragile X model. Mol. Psychiatry 22, 1140–1148 (2017).

    Google Scholar 

  189. 189

    Osterweil, E. K. et al. Lovastatin corrects excess protein synthesis and prevents epileptogenesis in a mouse model of fragile X syndrome. Neuron 77, 243–250 (2013).

    Google Scholar 

  190. 190

    Caku, A., Pellerin, D., Bouvier, P., Riou, E. & Corbin, F. Effect of lovastatin on behavior in children and adults with fragile X syndrome: an open-label study. Am. J. Med Genet. A 164A, 2834–2842 (2014).

    Google Scholar 

  191. 191

    Pellerin, D. et al. Lovastatin corrects ERK pathway hyperactivation in fragile X syndrome: potential of platelet's signaling cascades as new outcome measures in clinical trials. Biomarkers 21, 497–508 (2016).

    Google Scholar 

  192. 192

    Deacon, R. M. et al. NNZ-2566, a novel analog of (1–3) IGF-1, as a potential therapeutic agent for fragile X syndrome. Neuromolecular Med. 17, 71–82 (2015).

    Google Scholar 

  193. 193

    Deacon, R. M. et al. Nrf2, a novel therapeutic target in fragile X syndrome is modulated by NNZ2566. Genes Brain Behav.http://dx.doi.org/10.1111/gbb.12373 (2017).

  194. 194

    Berry-Kravis, E. et al. The treatment of fragile X syndrome with Trofinetide (NNZ-2566). Ann. Neurol. 80, S412 (2016).

    Google Scholar 

  195. 195

    Bailey, D. B., Raspa, M. & Olmsted, M. G. Using a parent survey to advance knowledge about the nature and consequences of fragile X syndrome. Am. J. Intellect. Dev. Disabil. 115, 447–460 (2010).

    Google Scholar 

  196. 196

    Chevreul, K. et al. Social/economic costs and health-related quality of life in patients with fragile X syndrome in Europe. Eur. J. Health Econom. 17 (Suppl. 1), 43–52 (2016). This paper described the burden and costs of FXS and suggested key outcomes that should change as a function of appropriate treatment.

    Google Scholar 

  197. 197

    Bailey, D. B. Jr ., Raspa, M., Olmsted, M. & Holiday, D. B. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am. J. Med Genet. A 146A, 2060–2069 (2008).

    Google Scholar 

  198. 198

    Chevreul, K., Berg Brigham, K., Brunn, M., des Portes, V. & Network, B.-R. R. Fragile X syndrome: economic burden and health-related quality of life of patients and caregivers in France. J. Intellect. Disabil. Res. 59, 1108–1120 (2015).

    Google Scholar 

  199. 199

    Bailey, D. B. Jr, Sideris, J., Roberts, J. & Hatton, D. Child and genetic variables associated with maternal adaptation to fragile X syndrome: a multidimensional analysis. Am. J. Med Genet. A 146A, 720–729 (2008).

    Google Scholar 

  200. 200

    Wheeler, A. C., Skinner, D. G. & Bailey, D. B. Perceived quality of life in mothers of children with fragile X syndrome. Am. J. Ment. Retard. 113, 159–177 (2008).

    Google Scholar 

  201. 201

    Raspa, M., Bailey, D. B. Jr, Bann, C. & Bishop, E. Modeling family adaptation to fragile X syndrome. Am. J. Intellect. Dev. Disabil. 119, 33–48 (2014).

    Google Scholar 

  202. 202

    Bailey, D. B. Jr . et al. Health and economic consequences of fragile X syndrome for caregivers. J. Dev. Behav. Pediatr. 33, 705–712 (2012).

    Google Scholar 

  203. 203

    Roberts, J. E. et al. Trajectory and predictors of depression and anxiety disorders in mothers with the FMR1 premutation. Biol. Psychiatry 79, 850–857 (2016). This paper provided the first insights into the longitudinal effects of premutation carrier status on depression and anxiety disorders.

    Google Scholar 

  204. 204

    Ouyang, L., Grosse, S., Raspa, M. & Bailey, D. Employment impact and financial burden for families of children with fragile X syndrome: findings from the National Fragile X Survey. J. Intellect. Disabil. Res. 54, 918–928 (2010).

    Google Scholar 

  205. 205

    Ouyang, L. et al. A comparison of family financial and employment impacts of fragile X syndrome, autism spectrum disorders, and intellectual disability. Res. Dev. Disabil. 35, 1518–1527 (2014).

    Google Scholar 

  206. 206

    Cross, J. et al. Caregiver preferences for the treatment of males with fragile X syndrome. J. Dev. Behav. Pediatr. 37, 71–79 (2016).

    Google Scholar 

  207. 207

    Berry-Kravis, E. et al. Development of an expressive language sampling procedure in fragile X syndrome: a pilot study. J. Dev. Behav. Pediatr. 34, 245–251 (2013).

    Google Scholar 

  208. 208

    Hessl, D. et al. The NIH Toolbox Cognitive Battery for intellectual disabilities: three preliminary studies and future directions. J. Neurodev. Disord. 8, 35 (2016).

    Google Scholar 

  209. 209

    Sansone, S. M. et al. Improving IQ measurement in intellectual disabilities using true deviation from population norms. J. Neurodev. Disord. 6, 16 (2014).

    Google Scholar 

  210. 210

    Sherman, S. et al. FORWARD: a registry and longitudinal clinical database to study fragile X syndrome. Pediatrics 139, S3 (2017).

    Google Scholar 

  211. 211

    Rogers, S. J. et al. Autism treatment in the first year of life: a pilot study of infant start, a parent-implemented intervention for symptomatic infants. J. Autism Dev. Disord. 44, 2981–2995 (2014).

    Google Scholar 

  212. 212

    Au, J. et al. A feasibility trial of Cogmed working memory training in fragile X syndrome. J. Pediatr. Genet. 3, 147–156 (2014).

    Google Scholar 

  213. 213

    Park, C. Y. et al. Reversion of FMR1 methylation and silencing by editing the triplet repeats in fragile X iPSC-derived neurons. Cell Rep. 13, 234–241 (2015).

    Google Scholar 

  214. 214

    Tassone, F. et al. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA 13, 555–562 (2007).

    Google Scholar 

  215. 215

    Tassone, F. et al. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am. J. Hum. Genet. 66, 6–15 (2000).

    Google Scholar 

  216. 216

    Hagerman, R. J. & Hagerman, P. Fragile X-associated tremor/ataxia syndrome — features, mechanisms and management. Nat. Rev. Neurol. 12, 403–412 (2016).

    Google Scholar 

  217. 217

    Sherman, S., Pletcher, B. A. & Driscoll, D. A. Fragile X syndrome: diagnostic and carrier testing. Genet. Med. 7, 584–587 (2005).

    Google Scholar 

  218. 218

    Hagerman, R. & Hagerman, P. Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol. 12, 786–798 (2013).

    Google Scholar 

  219. 219

    Darnell, J. C. et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell 146, 247–261 (2011).

    Google Scholar 

  220. 220

    Ascano, M. Jr et al. FMRP targets distinct mRNA sequence elements to regulate protein expression. Nature 492, 382–386 (2012).

    Google Scholar 

  221. 221

    Miyashiro, K. Y. et al. RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 37, 417–431 (2003).

    Google Scholar 

  222. 222

    Tang, B. et al. Fmr1 deficiency promotes age-dependent alterations in the cortical synaptic proteome. Proc. Natl Acad. Sci. USA 112, E4697–E4706 (2015).

    Google Scholar 

  223. 223

    Schenck, A., Bardoni, B., Moro, A., Bagni, C. & Mandel, J. L. A highly conserved protein family interacting with the fragile X mental retardation protein (FMRP) and displaying selective interactions with FMRP-related proteins FXR1P and FXR2P. Proc. Natl Acad. Sci. USA 98, 8844–8849 (2001).

    Google Scholar 

  224. 224

    Napoli, I. et al. The fragile X syndrome protein represses activity-dependent translation through CYFIP1, a new 4E-BP. Cell 134, 1042–1054 (2008).

    Google Scholar 

  225. 225

    Jin, P. et al. Biochemical and genetic interaction between the fragile X mental retardation protein and the microRNA pathway. Nat. Neurosci. 7, 113–117 (2004).

    Google Scholar 

  226. 226

    Muddashetty, R. S. et al. Reversible inhibition of PSD-95 mRNA translation by miR-125a, FMRP phosphorylation, and mGluR signaling. Mol. Cell 42, 673–688 (2011).

    Google Scholar 

  227. 227

    Bechara, E. G. et al. A novel function for fragile X mental retardation protein in translational activation. PLoS Biol. 7, e16 (2009).

    Google Scholar 

  228. 228

    Chen, E., Sharma, M. R., Shi, X., Agrawal, R. K. & Joseph, S. Fragile x mental retardation protein regulates translation by binding directly to the ribosome. Mol. Cell 54, 407–417 (2014).

    Google Scholar 

  229. 229

    Iossifov, I. et al. De novo gene disruptions in children on the autistic spectrum. Neuron 74, 285–299 (2012).

    Google Scholar 

  230. 230

    Boland, M. J. et al. Molecular analyses of neurogenic defects in a human pluripotent stem cell model of fragile X syndrome. Brain 140, 582–598 (2017).

    Google Scholar 

  231. 231

    Fatemi, S. H., Folsom, T. D., Rooney, R. J. & Thuras, P. D. mRNA and protein expression for novel GABAA receptors theta and rho2 are altered in schizophrenia and mood disorders; relevance to FMRP–mGluR5 signaling pathway. Transl Psychiatry 3, e271 (2013).

    Google Scholar 

  232. 232

    Fatemi, S. H., Kneeland, R. E., Liesch, S. B. & Folsom, T. D. Fragile X mental retardation protein levels are decreased in major psychiatric disorders. Schizophr. Res. 124, 246–247 (2010).

    Google Scholar 

  233. 233

    McDuffie, A., Thurman, A. J., Hagerman, R. J. & Abbeduto, L. Symptoms of Autism in males with fragile X syndrome: a comparison to nonsyndromic ASD using current ADI-R scores. J. Autism Dev. Disord. 45, 1925–1937 (2015).

    Google Scholar 

  234. 234

    Thurman, A. J., McDuffie, A., Hagerman, R. & Abbeduto, L. Psychiatric symptoms in boys with fragile X syndrome: a comparison with nonsyndromic autism spectrum disorder. Res. Dev. Disabil. 35, 1072–1086 (2014).

    Google Scholar 

  235. 235

    Talisa, V. B., Boyle, L., Crafa, D. & Kaufmann, W. E. Autism and anxiety in males with fragile X syndrome: an exploratory analysis of neurobehavioral profiles from a parent survey. Am. J. Med Genet. A 164A, 1198–1203 (2014).

    Google Scholar 

  236. 236

    Hardiman, R. L. & Bratt, A. Hypothalamic–pituitary–adrenal axis function in fragile X syndrome and its relationship to behaviour: a systematic review. Physiol. Behav. 167, 341–353 (2016).

    Google Scholar 

  237. 237

    Hessl, D., Rivera, S. M. & Reiss, A. L. The neuroanatomy and neuroendocrinology of fragile X syndrome. Ment. Retard. Dev. Disabil. Res. Rev. 10, 17–24 (2004).

    Google Scholar 

  238. 238

    Thurman, A. J., McDuffie, A., Hagerman, R. J., Josol, C. K. & Abbeduto, L. Language skills of males with fragile X syndrome or nonsyndromic autism spectrum disorder. J. Autism Dev. Disord. 47, 728–743 (2017).

    Google Scholar 

  239. 239

    Oberman, L. M. et al. Abnormal mechanisms of plasticity and metaplasticity in autism spectrum disorders and fragile X syndrome. J. Child Adolesc. Psychopharmacol. 26, 617–624 (2016).

    Google Scholar 

  240. 240

    Hartley, S. L. et al. Exploring the adult life of men and women with fragile X syndrome: results from a national survey. Am. J. Intellect. Dev. Disabil. 116, 16–35 (2011).

    Google Scholar 

  241. 241

    Wheeler, A. C., Raspa, M., Bishop, E. & Bailey, D. B. Jr . Aggression in fragile X syndrome. J. Intellect. Disabil. Res. 60, 113–125 (2016).

    Google Scholar 

  242. 242

    Raspberry, K. A. & Skinner, D. Negotiating desires and options: how mothers who carry the fragile X gene experience reproductive decisions. Soc. Sci. Med. 72, 992–998 (2011).

    Google Scholar 

  243. 243

    Raspa, M., Edwards, A., Wheeler, A. C., Bishop, E. & Bailey, D. B. Jr . Family communication and cascade testing for fragile X syndrome. J. Genet. Couns. 25, 1075–1084 (2016).

    Google Scholar 

  244. 244

    Wheeler, A. C. et al. Associated features in females with an FMR1 premutation. J. Neurodev. Disord. 6, 30 (2014).

    Google Scholar 

  245. 245

    Wheeler, A. C. et al. Health and reproductive experiences of women with an FMR1 premutation with and without fragile X premature ovarian insufficiency. Front. Genet. 5, 300 (2014).

    Google Scholar 

  246. 246

    Cornish, K., Cole, V., Longhi, E., Karmiloff-Smith, A. & Scerif, G. Mapping developmental trajectories of attention and working memory in fragile X syndrome: developmental freeze or developmental change? Dev. Psychopathol. 25, 365–376 (2013).

    Google Scholar 

  247. 247

    Cornish, K., Scerif, G. & Karmiloff-Smith, A. Tracing syndrome-specific trajectories of attention across the lifespan. Cortex 43, 672–685 (2007).

    Google Scholar 

  248. 248

    Musumeci, S. A. et al. Epilepsy and EEG findings in males with fragile X syndrome. Epilepsia 40, 1092–1099 (1999).

    Google Scholar 

  249. 249

    Roberts, J. E. et al. Autistic behavior in boys with fragile X syndrome: social approach and HPA-axis dysfunction. J. Neurodev. Disord. 1, 283–291 (2009).

    Google Scholar 

  250. 250

    de Vries, B. B. et al. Mental status of females with an FMR1 gene full mutation. Am. J. Hum. Genet. 58, 1025–1032 (1996).

    Google Scholar 

  251. 251

    Utari, A. et al. Aging in fragile X syndrome. J. Neurodev. Disord. 2, 70–76 (2010).

    Google Scholar 

  252. 252

    Abe, T. et al. Molecular characterization of a novel metabotropic glutamate receptor mGluR5 coupled to inositol phosphate/Ca2+ signal transduction. J. Biol. Chem. 267, 13361–13368 (1992).

    Google Scholar 

  253. 253

    Banko, J. L., Hou, L., Poulin, F., Sonenberg, N. & Klann, E. Regulation of eukaryotic initiation factor 4E by converging signaling pathways during metabotropic glutamate receptor-dependent long-term depression. J. Neurosci. 26, 2167–2173 (2006).

    Google Scholar 

  254. 254

    Tanimura, A. et al. The endocannabinoid 2-arachidonoylglycerol produced by diacylglycerol lipase alpha mediates retrograde suppression of synaptic transmission. Neuron 65, 320–327 (2010).

    Google Scholar 

  255. 255

    Deng, P. Y. & Klyachko, V. A. Increased persistent sodium current causes neuronal hyperexcitability in the entorhinal cortex of Fmr1 knockout mice. Cell Rep. 16, 3157–3166 (2016).

    Google Scholar 

  256. 256

    Osterweil, E. K., Krueger, D. D., Reinhold, K. & Bear, M. F. Hypersensitivity to mGluR5 and ERK1/2 leads to excessive protein synthesis in the hippocampus of a mouse model of fragile X syndrome. J. Neurosci. 30, 15616–15627 (2010).

    Google Scholar 

  257. 257

    Sharma, A. et al. Dysregulation of mTOR signaling in fragile X syndrome. J. Neurosci. 30, 694–702 (2010).

    Google Scholar 

  258. 258

    Gross, C. et al. Excess phosphoinositide 3-kinase subunit synthesis and activity as a novel therapeutic target in fragile X syndrome. J. Neurosci. 30, 10624–10638 (2010).

    Google Scholar 

  259. 259

    Chen, L. Y. et al. Physiological activation of synaptic Rac>PAK (p-21 activated kinase) signaling is defective in a mouse model of fragile X syndrome. J. Neurosci. 30, 10977–10984 (2010).

    Google Scholar 

  260. 260

    Almena, M. & Merida, I. Shaping up the membrane: diacylglycerol coordinates spatial orientation of signaling. Trends Biochem. Sci. 36, 593–603 (2011).

    Google Scholar 

  261. 261

    Ghosh, S. & Bell, R. M. Regulation of Raf-1 kinase by interaction with the lipid second messenger, phosphatidic acid. Biochem. Soc. Trans. 25, 561–565 (1997).

    Google Scholar 

  262. 262

    Stace, C. et al. PA binding of phosphatidylinositol 4-phosphate 5-kinase. Adv. Enzyme Regul. 48, 55–72 (2008).

    Google Scholar 

  263. 263

    Avila-Flores, A., Santos, T., Rincon, E. & Merida, I. Modulation of the mammalian target of rapamycin pathway by diacylglycerol kinase-produced phosphatidic acid. J. Biol. Chem. 280, 10091–10099 (2005).

    Google Scholar 

  264. 264

    Gantois, I. et al. Expression profiling suggests underexpression of the GABAA receptor subunit delta in the fragile X knockout mouse model. Neurobiol. Dis. 21, 346–357 (2006).

    Google Scholar 

  265. 265

    D’Hulst, C. et al. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res. 1121, 238–245 (2006). This was the first paper to demonstrate convincingly that GABAergic abnormalities underlie FXS.

    Google Scholar 

  266. 266

    Hong, A., Zhang, A., Ke, Y., El Idrissi, A. & Shen, C. H. Downregulation of GABAA beta subunits is transcriptionally controlled by Fmr1p. J. Mol. Neurosci. 46, 272–275 (2011).

    Google Scholar 

  267. 267

    El Idrissi, A. et al. Decreased GABAA receptor expression in the seizure-prone fragile X mouse. Neurosci. Lett. 377, 141–146 (2005).

    Google Scholar 

  268. 268

    Gatto, C. L., Pereira, D. & Broadie, K. GABAergic circuit dysfunction in the Drosophila fragile X syndrome model. Neurobiol. Dis. 65, 142–159 (2014).

    Google Scholar 

  269. 269

    Adusei, D. C., Pacey, L. K., Chen, D. & Hampson, D. R. Early developmental alterations in GABAergic protein expression in fragile X knockout mice. Neuropharmacology 59, 167–171 (2010).

    Google Scholar 

  270. 270

    Kratovac, S. & Corbin, J. G. Developmental changes in expression of inhibitory neuronal proteins in the fragile X syndrome mouse basolateral amygdala. Brain Res. 1537, 69–78 (2013).

    Google Scholar 

  271. 271

    D’Hulst, C. et al. Positron emission tomography (PET) quantification of GABAA receptors in the brain of fragile X patients. PLoS ONE 10, e0131486 (2015).

    Google Scholar 

  272. 272

    Kang, J. Y. et al. Deficits in the activity of presynaptic γ-aminobutyric acid type B receptors contribute to altered neuronal excitability in fragile X syndrome. J. Biol. Chem. 292, 6621–6632 (2017).

    Google Scholar 

  273. 273

    D’Hulst, C. et al. Expression of the GABAergic system in animal models for fragile X syndrome and fragile X associated tremor/ataxia syndrome (FXTAS). Brain Res. 1253, 176–183 (2009).

    Google Scholar 

  274. 274

    Davidovic, L. et al. A metabolomic and systems biology perspective on the brain of the fragile X syndrome mouse model. Genome Res. 21, 2190–2202 (2011).

    Google Scholar 

  275. 275

    Paluszkiewicz, S. M., Martin, B. S. & Huntsman, M. M. Fragile X syndrome: the GABAergic system and circuit dysfunction. Dev. Neurosci. 33, 349–364 (2011).

    Google Scholar 

  276. 276

    Gross, C., Hoffmann, A., Bassell, G. J. & Berry-Kravis, E. M. Therapeutic strategies in fragile X syndrome: from bench to bedside and back. Neurotherapeutics 12, 584–608 (2015). This was a comprehensive review of all preclinical work and targeted treatments in clinical trials for FXS, including outcome measures used and measures showing change.

    Google Scholar 

  277. 277

    Hoffmann, A. & Berry-Kravis, E. in Neuronal and Synaptic Dysfunction in Autism Spectrum Disorder and Intellectual Disability (eds Sala, C. & Verpelli, C. ) 325–346 (Academic Press, 2016).

    Google Scholar 

Download references

Acknowledgements

This work was supported by the following grants. R.J.H., P.J.H. and F.T. were funded by US Health Resources and Services Administration (HRSA) grant R40MC27701, National Institute of Child Health and Human Development grant R01HD036071, HRSA grant R40MC22641, Department of Defense grant PR101054, MIND Institute Intellectual and Developmental Disability Research Center U54HD07912. H.M. and L.M. are funded by Agence Nationale de la Recherche (ANR-12-BSV8-0022), Fondation Jérôme Lejeune funding, FRAXA Research Foundation and grant ANR-10-LABX-0030-INRT, a French State fund managed by the Agence Nationale de la Recherche under the frame programme Investissements d’Avenir ANR-10-IDEX-0002-02 to H.M. and J.L.M. R.F.K. is funded by grants from the Research Foundation Flanders, FRAXA Research Foundation and the Fondation Jérôme Lejeune. H.C.H. was funded by NICHD R01HD059854. The authors thank L. Makhoul for help with preparation of this manuscript.

Author information

Affiliations

Authors

Contributions

Introduction (R.J.H. and P.J.H.); Epidemiology (F.T.); Mechanisms/pathophysiology (J.L.M., H.M., R.F.K., N.S., H.C.H. and P.J.H.); Diagnosis, screening and prevention (R.J.H. and F.T.); Management (E.B.-K. and R.J.H.); Quality of life (D.B.B.); Outlook (R.J.H., E.B.-K. and P.J.H); Overview of Primer (R.J.H. and P.J.H.).

Corresponding author

Correspondence to Randi J. Hagerman.

Ethics declarations

Competing interests

R.J.H. has received funding from Novartis, Roche, Alcobra, Neuren and Marinus for clinical trials in FXS and has consulted with Zynerba for clinical trials in FXS. E.B.-K. has received funding from Novartis, Roche, Alcobra, Neuren, Cydan, Fulcrum, GW, Marinus, Edison and Neurotrope Pharmaceuticals to consult on trial design and development strategies and/or conduct clinical trials in FXS, and from Asuragen Inc. to develop testing standards for FMR1 testing. D.B.B. received funding from The John Merck Fund to plan a fragile X newborn screening study. R.F.K. has received logistic support and ganaxolone treatment funding from Marinus Pharmaceuticals to conduct a clinical trial in FXS. F.T. has received funding for molecular studies in FXS from Asuragen. All other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and Permissions

About this article

Verify currency and authenticity via CrossMark

Cite this article

Hagerman, R., Berry-Kravis, E., Hazlett, H. et al. Fragile X syndrome. Nat Rev Dis Primers 3, 17065 (2017). https://doi.org/10.1038/nrdp.2017.65

Download citation

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing