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Fragile X-associated disorders: a clinical overview

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Abstract

Fragile X Syndrome (FraX) is the most common inherited cause of learning disability worldwide. FraX is an X-linked neuro-developmental disorder involving an unstable trinucleotide repeat expansion of cytosine guanine guanine (CGG). Individuals with the full mutation of FraX have >200 CGG repeats with premutation carriers having 55–200 CGG repeats. A wide spectrum of physical, behavioural, cognitive, psychiatric and medical problems have been associated with both full mutation and premutation carriers of FraX. In this review, we detail the clinical profile and examine the aetiology, epidemiology, neuropathology, neuroimaging findings and possible management strategies for individuals with both the full mutation and premutation of FraX.

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References

  1. Fernandez-Carvajal I, Walichiewicz P, Xiaosen X et al (2009) Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 11:324–328

    PubMed  CAS  Google Scholar 

  2. Crawford DC, Meadows KL, Newman JL et al (2002) Prevalence of the fragile X syndrome in African Americans. Am J Med Genet 110:226–233

    PubMed  Google Scholar 

  3. Pesso R, Berkenstadt M, Cuckle H et al (2000) Screening for fragile X syndrome in women of reproductive age. Prenat Diagn 20:611–614

    PubMed  CAS  Google Scholar 

  4. Hagerman R, Hagerman P (2002) The fragile X premutation: into the phenotypic fold. Curr Opin Genet Dev 12:278–283

    PubMed  CAS  Google Scholar 

  5. Toledano-Alhadef H, Basel-Vanagaite L, Magal N et al (2001) Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 69:351–360

    PubMed  CAS  Google Scholar 

  6. Rousseau F, Rouillard P, Morel ML, Khandjian EW, Morgan K (1995) Prevalence of carriers of premutation-size alleles of the FMR1 gene—and implications for the population genetics of the fragile X syndrome. Am J Hum Genet 57:1006–1018

    PubMed  CAS  Google Scholar 

  7. Dombrowski C, Lévesque S, Morel ML, Rouillard P, Morgan K, Rousseau F (2002) Premutation and intermediate-size FMR1 alleles in 10572 males from the general population: loss of an AGG interruption is a late event in the generation of fragile X syndrome alleles. Hum Mol Genet 11:371–378

    PubMed  CAS  Google Scholar 

  8. Tzeng C, Tsai L, Hwu W et al (2005) Prevalence of the FMR1 mutation in Taiwan assessed by large-scale screening of newborn boys and analysis of DXS548 FRAXAC1 haplotype. Am J Med Genet A 133:37–43

    Google Scholar 

  9. Grigsby JP, Kemper MB, Hagerman RJ, Myers CS (1990) Neuropsychological dysfunction among affected heterozygous fragile X females. Am J Med Genet 35:28–35

    PubMed  CAS  Google Scholar 

  10. Grigsby J, Kemper MB, Hagerman RJ (1992) Verbal learning and memory among heterozygous fragile X females. Am J Med Genet 43:111–115

    PubMed  CAS  Google Scholar 

  11. Mazzocco MM, Pennington BF, Hagerman RJ (1993) The neurocognitive phenotype of female carriers of fragile X: additional evidence for specificity. J Dev Behav Pediatr 14:328–335

    PubMed  CAS  Google Scholar 

  12. Verkerk AJMH, Pieretti M, Sutcliffe JS et al (1991) Identification of a gene (FMR1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 65:905–914

    Google Scholar 

  13. Yu S, Pritchard M, Kremer E et al (1991) Fragile-X genotype characterized by an unstable region of DNA. Science 252:1179–1181

    CAS  Google Scholar 

  14. Van der Molen M, Huizinga M, Huizenga HM et al (2010) Profiling fragile X syndrome in males: strengths and weaknesses in cognitive abilities. Res Dev Disabil 31:426–439

    PubMed  Google Scholar 

  15. Mandel JL, Biancalana V (2004) Fragile X mental retardation syndrome: from pathogenesis to diagnostic issues. Growth Horm IGF Res 14(Suppl A):S158–S165

    PubMed  CAS  Google Scholar 

  16. Hagerman R, Hagerman P (eds) (2002) Fragile X syndrome: diagnosis, treatment and research, 3rd edn. John Hopkins University Press, Baltimore, pp 3–109

    Google Scholar 

  17. Meryash DL, Cronk CE, Sachs B, Gerald PS (1984) An anthropometric study of males with the fragile-X syndrome. Am J Med Genet 17:159–174

    PubMed  CAS  Google Scholar 

  18. Hagerman RJ (2002) Physical and behavioural phenotype. In: Hagerman RJ, Hagerman P (eds) Fragile X syndrome: diagnosis, treatment and research, 3rd edn. The Johns Hopkins University Press, Baltimore, pp 3–109

    Google Scholar 

  19. Chonchaiya W, Schneider A, Hagerman RJ (2009) Fragile X: a family of disorders. Adv Pediatr 56:165–186

    PubMed  Google Scholar 

  20. Berry-Kravis E (2002) Epilepsy in fragile X syndrome. Dev Med Child Neurol 42:724–728

    Google Scholar 

  21. Jacquemont S, Hagerman RJ, Hagerman P, Leehey M (2007) Fragile-X syndrome and fragile X-associated tremor/ataxia syndrome: two faces of FMR1. Lancet Neurol 6:45–55

    PubMed  CAS  Google Scholar 

  22. Reiss AL, Freund LS (1990) Fragile X syndrome, DSM-III-R, and autism. J Am Acad Child Adolesc Psychiatry 29:885–891

    PubMed  CAS  Google Scholar 

  23. Scharfenaker S, O’Connor R, Stackhouse R et al (1996) An integrated approach to intervention. In: Hagerman R, Cronister A (eds) Fragile X syndrome: diagnosis treatment and research. The Johns Hopkins University Press, Baltimore, pp 349–411

    Google Scholar 

  24. Levitas A (1996) Neuropsychiatric aspects of fragile X syndrome. Semin Clin Neuropsychiatry 1:154–167

    PubMed  Google Scholar 

  25. Lachiewicz AM, Spiridigliozzi GA, Gullion CM et al (1994) Aberrant behaviours of young boys with fragile X syndrome. Am J Ment Retard 98:567–579

    PubMed  CAS  Google Scholar 

  26. Hatton D, Sideris J, Skinner M et al (2006) Autistic behaviour in children with fragile X syndrome: prevalence, stability, and the impact of FMRP. Am J Med Genet 140:1804–1813

    Google Scholar 

  27. Kaufmann WE, Cortell R, Kau AS et al (2004) Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet 129A:225–234

    PubMed  Google Scholar 

  28. Rogers SJ, Wehner EA, Hagerman RJ et al (2001) The behavioural phenotype in fragile X: symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. J Dev Behav Pediatr 22:409–417

    PubMed  CAS  Google Scholar 

  29. Harris S, Hessl D, Goodlin-Jones B et al (2008) Autism profiles of males with fragile x syndrome. Am J Ment Retard 113:427–438

    Google Scholar 

  30. Demark JL, Feldman MA, Holden JJ (2003) Behavioural relationship between autism and fragile X syndrome. Am J Ment Retard 108:314–326

    PubMed  Google Scholar 

  31. Bailey DB, Mesibov GB, Hatton DD et al (1998) Autistic behaviour in young boys with fragile X syndrome. J Autism Dev Disord 28:6

    Google Scholar 

  32. Hessl D, Tassone F, Cordeiro L et al (2008) Brief report: aggression and stereotypic behaviour in males with fragile X syndrome—moderating secondary genes in a “single gene” disorder. J Autism Dev Disord 38:184–189

    PubMed  Google Scholar 

  33. Tsiouris JA, Brown WT (2004) Neuropsychiatric symptoms of fragile X syndrome: pathophysiology and pharmacotherapy. CNS Drugs 18:687–703

    PubMed  CAS  Google Scholar 

  34. Hagerman RJ, Hills J, Scharfnaker S et al (1999) Fragile X syndrome and selective mutism. Am J Med Genet 83:313–317

    PubMed  CAS  Google Scholar 

  35. Cordeiro L, Ballinger E, Hagerman R, Hessl D (2011) Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodev Disord 3:1–11

    CAS  Google Scholar 

  36. Hagerman R, Kemper M, Hudson M (1985) Learning disabilities and attentional problems in boys with the fragile X syndrome. Am J Dis Child 139:674–678

    PubMed  CAS  Google Scholar 

  37. Hessl D, Nguyen DV, Green C et al (2008) A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome. J Neurodev Disord 1:33–45

    Google Scholar 

  38. Dykens EM, Hoddap RM, Leckman JF (1987) Strengths and weaknesses in the intellectual functioning of males with fragile X syndrome. Am J Med Genet 28:13–15

    Google Scholar 

  39. Freund LS, Reiss AL (1991) Cognitive profiles associated with the fragile X syndrome in males and females. Am J Med Genet 38:542–547

    PubMed  CAS  Google Scholar 

  40. Kemper MB, Hagerman RJ, Ahmad RS, Mariner R (1986) Cognitive profiles and the spectrum of clinical manifestations in heterozygous fragile X females. Am J Med Genet 23:139–156

    PubMed  CAS  Google Scholar 

  41. Cornish KM, Munira F, Cross G (1999) Spatial cognition in males with fragile X syndrome: evidence for a neuropsychological phenotype. Cortex 35:263–271

    Google Scholar 

  42. Shapiro MB, Murphy DGM, Hagerman RJ et al (1995) Adult fragile X syndrome: neuropsychology, brain anatomy and metabolism. Am J Med Genet 60:480–493

    Google Scholar 

  43. Munir F, Cornish K, Wilding J (2000) A neuropsychological profile of attention deficits in young males with fragile X syndrome. Neuropsychologia 38:1261–1270

    PubMed  CAS  Google Scholar 

  44. Kaufman PM, Leckman JF, Ort SI (1990) Delayed response performance in males with fragile X syndrome. J Clin Exp Neuropsychol 12:69

    Google Scholar 

  45. Munir F, Cornish KM, Wilding J (2000) Nature of the working memory deficit in fragile X syndrome. Brain Cogn 44:387–401

    Google Scholar 

  46. Escalante JA, Grunspun H, Frota-Pessoa O (1971) Severe sex-linked mental retardation. J Genet Hum 19:137–140

    Google Scholar 

  47. Loesch DZ, Hay DA (1988) Clinical features and reproductive patterns in fragile X female heterozygotes. J Med Genet 25:407–414

    PubMed  CAS  Google Scholar 

  48. Hagerman RJ, Jackson C, Amiri K et al (1992) Girls with fragile X syndrome: physical and neurocognitive status and outcome. Pediatrics 89:395–400

    PubMed  CAS  Google Scholar 

  49. Moore PS, Chudley AE, Winter JS (1990) True precocious puberty in a girl with the fragile X syndrome. Am J Med Genet 37:265–267

    PubMed  CAS  Google Scholar 

  50. Riddle JE, Cheema A, Sobesky WE et al (1998) Phenotypic involvement in females with the FMR1 gene mutation. Am J Ment Retard 102:590–601

    PubMed  CAS  Google Scholar 

  51. Tassone F, Hagerman RJ, Ikle DN et al (1999) FMR1 protein expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet 84:250–261

    PubMed  CAS  Google Scholar 

  52. Loesch DZ, Huggins RM, Hagerman RJ (2004) Phenotypic variation and FMR1 protein levels in fragile X. Med Retard Dev Disabil Res Rev 10:31–41

    Google Scholar 

  53. Dyer-Friedman J, Glaser B, Hessl D et al (2002) Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome. J Am Acad Child Adolesc Psychiatry 41(3):237–244

    PubMed  Google Scholar 

  54. Reiss AL, Freund LS, Baumgardner TL, Abrams MT, Denckla MB (1995) Contribution of the FMR1 gene mutation to human intellectual dysfunction. Nat Genet 11:331–334

    PubMed  CAS  Google Scholar 

  55. Freund L, Reiss AL, Abrams M (1993) Psychiatric disorders associate with fragile X in the young female. Paediatrics 91:321–329

    CAS  Google Scholar 

  56. Kaplan SC, Hong GK, Weinhold C (1986) Epidemiology of depressive symptomatology in adolescents. Am J Psychiatry 18:343–354

    Google Scholar 

  57. Roberts JE, Bailey DB Jr, Mankowski J et al (2009) Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet 150B:130–139

    PubMed  Google Scholar 

  58. Reiss AL, Hagerman RJ, Vingradov S, Abrams M, King RJ (1988) Psychiatric disability in female carriers of the fragile X chromosome. Arch Gen Psychiatry 45:25–30

    PubMed  CAS  Google Scholar 

  59. Freund LS, Reiss AL (1992) Chromosome fragility and psychopathology in obligate female carriers of the fragile X chromosome. Arch Gen Psychiatry 49:54–60

    PubMed  CAS  Google Scholar 

  60. Hagerman RJ, Staley LW, O’Connor R et al (1996) Learning disabled males with a fragile X CGG expansion in the upper premutation range. Paediatrics 97:122–126

    CAS  Google Scholar 

  61. Loesch DZ, Hay DA, Mulley JC (1994) Transmitting males and carrier females in fragile X revisited. Am J Med Genet 51:392–399

    PubMed  CAS  Google Scholar 

  62. Moore CJ, Daly EM, Tassone F et al (2004) The effect of pre-mutation of X chromosome CGG trinucleotide repeats on brain anatomy. Brain 127:2672–2681

    PubMed  Google Scholar 

  63. Dorn MB, Mazzocco MM, Hagerman RJ (1994) Behavioural and psychiatric disorders in adult male carriers of fragile X. J Am Acad Child Adolesc Psychiatry 33:256–264

    PubMed  CAS  Google Scholar 

  64. Farzin F, Perry H, Hessl D et al (2006) Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr 27(2):S137–S144

    PubMed  Google Scholar 

  65. Aziz M, Stathopulu E, Callias M et al (2003) Clinical features of boys with fragile X premutations and intermediate alleles. Am J Med Genet 121B(1):119–127

    PubMed  Google Scholar 

  66. Goodlin-Jones B, Tassone F, Gane LW, Hagerman RJ (2004) Autistic spectrum disorder and the fragile X premutation. J Dev Behav Pediatr 25(6):392–398

    PubMed  Google Scholar 

  67. Cornish KM, Kogan C, Turk J et al (2005) The emerging fragile X premutation phenotype: evidence from the domain of social cognition. Brain Cogn 57(1):53–60

    PubMed  Google Scholar 

  68. Bailey DB Jr, Hatton DD, Mesibov GB, Ament N, Skinner M (2000) Early development, temperament and functional impairment in autism and fragile X syndrome. J Autism Dev Disord 30:49–59

    PubMed  Google Scholar 

  69. Bourgeois JA, Coffey SM, Rivera SM et al (2009) A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 70(6):852–862

    PubMed  CAS  Google Scholar 

  70. Hull C, Hagerman RJ (1993) A study of the physical, behavioural, and medical phenotype, including anthropometric measures of females with fragile X syndrome. Am J Dis Child 147:1236–1241

    PubMed  CAS  Google Scholar 

  71. Bennetto L, Pennington BF (2002) Neuropsychology. In: Hagerman RJ, Hagerman PJ (eds) Fragile X syndrome: diagnosis, treatment and research, 3rd edn. The Johns Hopkins University Press, Baltimore

    Google Scholar 

  72. Franke P, Leboyer M, Gansicke M et al (1998) Genotype-phenotype relationship in female carriers of the premutation and full mutation of FMR-1. Psychiatry Res 80:113–127

    PubMed  CAS  Google Scholar 

  73. Rodriguez-Revenga L, Madrigal I, Pagonabarraga J et al (2009) Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet 17:1359–1362

    PubMed  CAS  Google Scholar 

  74. Constant EL, Adam S, Seron X et al (2005) Anxiety and depression, attention, and executive functions in hypothyroidism. J Int Neuropsychol Soc 11:535–544

    PubMed  CAS  Google Scholar 

  75. Larisch R, Kley K, Nikolaus S et al (2004) Depression and anxiety in different thyroid function states. Horm Metab Res 36:650–653

    PubMed  CAS  Google Scholar 

  76. Hundscheid RD, Braat DD, Kiemeney LA et al (2001) Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives. Human Reprod 16:457–462

    CAS  Google Scholar 

  77. Allingham-Hawkins DJ, Brown CA, Babul R et al (1999) Fragile X premutation is a significant risk factor for premature ovarian failure. The international collaborative POF in fragile X study—preliminary data. Am J Med Genet 83:322–325

    PubMed  CAS  Google Scholar 

  78. Hagerman RJ, Leehey M, Heinrichs W et al (2001) Intention tremor, Parkinsonism and generalized brain atrophy in older male carriers of fragile X. Neurology 57:127–130

    PubMed  CAS  Google Scholar 

  79. Jacquemont S, Hagerman RJ, Leehey M et al (2003) Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet 72:869–878

    PubMed  CAS  Google Scholar 

  80. Leehey MA, Munhoz RP, Lang AE et al (2003) The fragile X premutation presenting as essential tremor. AMA Arch Neurol 60:117–121

    PubMed  Google Scholar 

  81. Coffey SM, Cook K, Tartaglia N et al (2008) Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet 146A:1009–1016

    PubMed  Google Scholar 

  82. Cornish KM, Kogan CS, Li L et al (2009) Lifespan changes in working memory in fragile X premutation males. Brain Cogn 69:551–558

    PubMed  Google Scholar 

  83. Hunter JE, Allen EG, Ann Abramowitz A et al (2008) No evidence for a difference in neuropsychological profile among carriers and non-carriers of the FMR1 premutation in adults under the age of 50. Am J Hum Genet 83:692–702

    PubMed  CAS  Google Scholar 

  84. Conway GS, Hettitarachein S, Murray A, Jacobs PA (1995) Fragile X premutations in familial premature ovarian failure. Lancet 346:309–310

    PubMed  CAS  Google Scholar 

  85. Sherman SL (2000) Premature ovarian failure in the fragile X syndrome. Am J Med Genet 97:189–194

    PubMed  CAS  Google Scholar 

  86. Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ (2000) 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

    PubMed  CAS  Google Scholar 

  87. Stevenson RE, Schwartz CE, Schroer RJ (2000) X-linked mental retardation. Oxford University Press, New York

    Google Scholar 

  88. Lubs H (1969) A marker X chromosome. Am J Hum Genet 21:231–244

    PubMed  CAS  Google Scholar 

  89. Sutherland GR (1977) Fragile sites on human chromosomes: demonstration of their dependence on the type of tissue culture medium. Science 197:265–266

    PubMed  CAS  Google Scholar 

  90. Merenstein SA, Sobesky WE, Taylor AK et al (1996) Molecular clinical correlations in males with an expanded FMR1 mutation. Am J Med Genet 64:388–394

    PubMed  CAS  Google Scholar 

  91. Reddy KS (2005) Cytogenetic abnormalities and fragile-X syndrome in autism spectrum disorder. BMC Med Genet 18:3

    Google Scholar 

  92. Nolin SL, Brown WT, Glicksman A et al (2003) Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet 72:454–464

    PubMed  CAS  Google Scholar 

  93. Zalfa F, Bagni C (2004) Molecular insights into mental retardation: multiple functions for the fragile X mental retardation protein? Curr Issues Mol Biol 6:73–88

    PubMed  CAS  Google Scholar 

  94. Abitbol M, Menini C, Delezoide AL et al (1993) Nucleus basalis magnocellularis and hippocampus are the major sites of FMR1 expression in the human fetal brain. Nat Genet 4:147–153

    PubMed  CAS  Google Scholar 

  95. Hinds HL, Ashley CT, Sutcliffe JS et al (1993) Tissue specific expression of FMR1 provides evidence for a functional role in fragile X syndrome. Nat Genet 3:36–43

    PubMed  CAS  Google Scholar 

  96. Zhang Y, O’Connor P, Siomi M et al (1995) The fragile X mental retardation syndrome protein interacts with novel homologs FXR1 and FXR2. EMBO J 14:5358–5366

    PubMed  CAS  Google Scholar 

  97. Eberhart DE, Malter HE, Feng Y, Warren ST (1996) The fragile X mental retardation protein is a ribonucleoprotein containing both nuclear localization and nuclear export signals. Hum Mol Genet 5:1083–1091

    PubMed  CAS  Google Scholar 

  98. Adinolfi S, Bagni C, Musco G et al (1999) Dissecting FMR1, the protein responsible for fragile X syndrome, in its structural and functional domains. RNA 5:1248–1258

    PubMed  CAS  Google Scholar 

  99. Schaeffer C, Beaulande M, Ehresmann C et al (2003) The RNA binding protein FMRP: new connections and missing links. Biol Cell 95:221–228

    PubMed  CAS  Google Scholar 

  100. Ceman S, Brown V, Warren ST (1999) Isolation of an FMRP-associated messenger ribonucleoprotein particle and identification of nucleolin and the fragile X related proteins as components of the complex. Mol Cell Biol 19:7925–7932

    PubMed  CAS  Google Scholar 

  101. Carola JM, Mcllwain KL, Nieuwenhuien IM et al (2002) Knockout mouse model for FXR2: a model for mental retardation. Hum Mol Genet 11:487–498

    Google Scholar 

  102. Broadie V, Pan L (2005) Translational complexity of the fragile X mental retardation protein: insights form the fly. Mol Cell 17:757–759

    PubMed  CAS  Google Scholar 

  103. Bilousova TV, Dansie L, Ngo M et al (2009) Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 46:94–102

    PubMed  CAS  Google Scholar 

  104. Antar LN, Li C, Zhang H, Carroll RC, Bassell GC (2006) Local functions for FMRP in axon growth cone motility and activity-dependent regulation of filopodia and spine synapses. Mol Cell Neurosci 32:37–48

    PubMed  CAS  Google Scholar 

  105. Gantois I, Vandesompele J, Speleman F et al (2006) Expression profiling reveals underexpression of the GABAA receptor subunit delta in the fragile X knockout mice model. Neurobiol Dis 21:346–357

    PubMed  CAS  Google Scholar 

  106. Mihalek RM, Banerjee PK, Korpi ER et al (1999) Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci USA 96:12905–12910

    PubMed  CAS  Google Scholar 

  107. D’Hulst C, De Geest N, Reeve SP et al (2006) Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res 1121:238–245

    PubMed  Google Scholar 

  108. D’Hulst C, De Geestb N, Reeveb S et al (2009) Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res 1253:176–183

    PubMed  Google Scholar 

  109. Huber KM, Kayser MS, Bear MF (2000) Role for rapid dendritic protein synthesis in hippocampal mGluR-dependent long-term depression. Science 288:1254–1257

    PubMed  CAS  Google Scholar 

  110. Huber KM, Roder JC, Bear MF (2001) Chemical induction of mGluR5- and protein synthesis-dependent long-term depression in hippocampal area CA1. J Neurophysiol 86:321–325

    PubMed  CAS  Google Scholar 

  111. Greenough WT, Klintsova AY, Irwin SA et al (2001) Synaptic regulation of protein synthesis and the fragile X protein. Proc Natl Acad Sci USA 98:7101–7106

    PubMed  CAS  Google Scholar 

  112. Weiler IJ, Irwin SA, Klintsova AY et al (1997) Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation. Proc Natl Acad Sci USA 94:5395–5400

    PubMed  CAS  Google Scholar 

  113. Grossman AW, Aldridge GM, Weiler IJ, Greenough WT (2006) Local protein synthesis and spine morphogenesis: fragile X syndrome and beyond. J Neurosci 26:7151–7155

    PubMed  CAS  Google Scholar 

  114. Aschrafi A, Cunningham BA, Edelman GM, Vanderklish PW (2005) The fragile X mental retardation protein and group I metabotropic glutamate receptors regulate levels of mRNA granules in brain. Proc Natl Acad Sci USA 102:2180–2185

    PubMed  CAS  Google Scholar 

  115. Bear MF, Dolen G, Osterweil E, Nagarajan N (2008) Fragile X: translation in action. Neuropsychopharmacology 33:84–87

    PubMed  CAS  Google Scholar 

  116. Bear MF, Huber KM, Warren ST (2004) The mGluR theory of fragile X mental retardation. Trends Neurosci 27:370–377

    PubMed  CAS  Google Scholar 

  117. Silverman JL, Tolu S, Barkan C, Crawley J (2010) Repetitive self-grooming behavior in the BTBR mouse model of autism is blocked by the mGluR5 antagonist MPEP. Neuropsychopharmacology 35:976–989

    PubMed  CAS  Google Scholar 

  118. Jacquemont S, Curie A, des Portes V et al (2011) Epigenetic modification of the FMR1 gene in fragile X syndrome is associated with differential response to the mGluR5 antagonist AFQ056. Sci Transl Med 3(64):64ra1

    PubMed  CAS  Google Scholar 

  119. Friedmann C, Davis L, Ciccone P, Rubin R (1980) Phase II double-blind controlled study of a new anxiolytic, fenobam (McN-3377) vs placebo. Curr Ther Res 27:144–151

    Google Scholar 

  120. Pecknold JC, McClure DJ, Appeltauer L, Wrzesinski L, Allan T (1982) Treatment of anxiety using fenobam (a nonbenzodiazepine) in a double-blind standard (diazepam) placebo-controlled study. J Clin Psychopharmacol 2:129–133

    PubMed  CAS  Google Scholar 

  121. Berry-Kravis E, Hessl D, Coffey S et al (2009) A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 46:266–271

    PubMed  CAS  Google Scholar 

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

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  124. Irwin SA, Idupulapati M, Gilbert ME et al (2002) Dendritic spine and dendritic field characteristics of layer V pyramidal neurons in the visual cortex of fragile-X knockout mice. Am J Med Genet 111:140–146

    PubMed  Google Scholar 

  125. Irwin SA, Patel B, Idupulapati M et al (2001) Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet 98:161–167

    PubMed  CAS  Google Scholar 

  126. Hinton VJ, Brown WT, Wisniewski K, Rudelli RD (1991) Analysis of neocortex in three males with fragile X syndrome. Am J Med Genet 41:289–294

    PubMed  CAS  Google Scholar 

  127. Irwin SA, Galvez R, Greenough WT (2000) Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex 10:1038–1044

    PubMed  CAS  Google Scholar 

  128. Koukoui SD, Chaudhuri A (2007) Neuroanatomical, molecular, genetic, and behavioural correlates of fragile X syndrome. Brain Res Rev 53:27–38

    PubMed  CAS  Google Scholar 

  129. Pfeiffer BE, Huber KM (2007) Fragile X mental retardation protein induces synapse loss through acute postsynaptic translational regulation. J Neurosci 27:3120–3130

    PubMed  CAS  Google Scholar 

  130. Pfeiffer BE, Zang T, Wilkerson JR et al (2010) Fragile X mental retardation protein is required for synapse elimination by the activity-dependent transcription factor MEF2. Neuron 66:191–197

    PubMed  CAS  Google Scholar 

  131. Greco CM, Berman RF, Martin RM et al (2006) Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 129:243–255

    PubMed  CAS  Google Scholar 

  132. Tassone F, Iwahahi C, Hagerman PJ (2004) FMR1 RNA within the intranuclear inclusions of Fragile X associated tremor/ataxia syndrome. RNA Biol 1:103–105

    PubMed  CAS  Google Scholar 

  133. Greco C, Hagerman RJ, Tassone F et al (2002) Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 125:1760–1771

    PubMed  CAS  Google Scholar 

  134. Reiss AL, Abrams MT, Greenlaw R, Freund L, Denckla MB (1995) Neurodevelopmental effects of the FMR1 full mutation in humans. Nat Med 1:159–167

    PubMed  CAS  Google Scholar 

  135. Eliez S, Blasey CM, Freund LS et al (2001) Brain anatomy, gender and IQ in children and adolescents with fragile X syndrome. Brain 124:168–1610

    Google Scholar 

  136. Gothelf D, Furfaro JA, Hoeft F et al (2008) Neuroanatomy of fragile X syndrome is associated with aberrant behaviour and the fragile X mental retardation protein (FMR1 PROTEIN). Ann Neurol 63:40–51

    PubMed  Google Scholar 

  137. Hoeft F, Lightbody AA, Hazlett HC et al (2008) Morpohometric spatial patterns differentiating boys with fragile X syndrome, typically developing boys, developmentally delayed boys aged 1 to 3 years. Arch Gen Psychiatry 65:1087–1097

    PubMed  Google Scholar 

  138. Hazlett HC, Poe MD, Lightbody AA et al (2009) Teasing apart the heterogeneity of autism: same behaviour, different brains in toddlers with fragile X syndrome and autism. J Neurodev Disord 1:181–190

    Google Scholar 

  139. Hallahan B, Craig M, Toal F et al (2010) In vivo brain anatomy of adult males with fragile X syndrome: an MRI study. Neuroimage 54:16–24

    PubMed  Google Scholar 

  140. Wilson LB, Tregellas JR, Hagerman RJ et al (2009) A voxel-based morphometry comparison of regional gray matter between fragile X syndrome and autism. Psychiatry Res 174:138–145

    PubMed  Google Scholar 

  141. Mostofsky SH, Mazzocco MM, Aakalu G et al (1998) Decreased cerebellar posterior vermis size in fragile X syndrome: correlation with neurocognitive performance. Neurology 51:121–130

    Google Scholar 

  142. Reiss AL, Aylward E, Freund LS et al (1991) Neuroanatomy of fragile X syndrome: the posterior fossa. Ann Neurol 29:26–32

    PubMed  CAS  Google Scholar 

  143. Reiss AL, Abrams MT, Greenlaw R et al (1995) Neurodevelopmental effects of the FMR-1 full mutation in humans. Nat Med 1:159–167

    PubMed  CAS  Google Scholar 

  144. Guerreiro MM, Camargo EE, Kato M et al (1998) Fragile X syndrome, Clinical, electroencephalographic and neuroimaging characteristics. Aq Neuropsiquiatr 56:18–23

    CAS  Google Scholar 

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

    PubMed  CAS  Google Scholar 

  146. Kates WR, Abrams MT, Kaufmann WE, Breiter SN, Reiss AL (1997) Reliability and validity of MRI measurement of the amygdala and hippocampus in children with fragile X syndrome. Psychiatry Res 76:15–27

    PubMed  Google Scholar 

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

    PubMed  Google Scholar 

  148. Cornish KM, Munira F, Cross G (2001) Differential impact of the FMR1 full mutation on memory and attention functioning: a neuropsychological perspective. J Cogn Neurosci 13:144–150

    PubMed  CAS  Google Scholar 

  149. Hoeft F, Hernandez A, Sudharshan P et al (2007) Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndrome. Hum Brain Map 28:543–554

    Google Scholar 

  150. Allen G, Buxton R, Wong EC, Courchesne E (1997) Attentional activation of the cerebellum independent of motor involvement. Science 275:1940–1943

    PubMed  CAS  Google Scholar 

  151. Townsend J, Courchesne E, Covington J et al (1999) Spatial attention deficits in patients with acquired or developmental cerebellar abnormality. J Neurosci 19:5632–5643

    PubMed  CAS  Google Scholar 

  152. Ronning C, Sundet K, Due-Tonnessen B et al (2005) Persistent cognitive dysfunction secondary to cerebellar injury in patients treated for posterior fossa tumors in childhood. Pediatr Neurosurg 41:15–21

    PubMed  Google Scholar 

  153. Brunberg JA, Jacquemont S, Hagerman RJ et al (2002) Fragile X permutation carriers: characteristic MR imaging findings in adult males with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 23:1757–1766

    PubMed  Google Scholar 

  154. Loesch DZ, Litewka L, Brotchie P et al (2005) Magnetic resonance imaging study in older fragile X premutation male carriers. Ann Neurol 58:326–330

    PubMed  CAS  Google Scholar 

  155. Cohen S, Masyn K, Adams J et al (2006) Molecular and imaging correlates of the fragile X-associated tremor/ataxia syndrome. Neurology 67:1426–1431

    PubMed  CAS  Google Scholar 

  156. Adams JS, Adams PE, Nguyen D et al (2007) Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 69:851–859

    PubMed  CAS  Google Scholar 

  157. Koldewyn K, Hessl D, Adams J et al (2008) Reduced hippocampal activation during recall is associated with elevated FMR1 mRNA and psychiatric symptoms in men with the fragile X premutation. Brain Imaging Behav 2:105–116

    PubMed  Google Scholar 

  158. Hessl D, Rivera S, Koldewyn K et al (2007) Amygdala dysfunction in men with the fragile X premutation. Brain 130:404–416

    PubMed  Google Scholar 

  159. Adams PE, Adams JS, Nguyen DV et al (2010) Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers. Am J Med Genet Part B 153B:775–785

    PubMed  CAS  Google Scholar 

  160. Oberle I, Rousseau F, Heitz D et al (1991) Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science 252:1097–1102

    CAS  Google Scholar 

  161. Willemsen R, Oosterwijk JC, Los FJ et al (1996) Prenatal diagnosis of fragile X syndrome. Lancet 348:967–968

    PubMed  CAS  Google Scholar 

  162. Iwahashi C, Tassone F, Hagerman RJ et al (2009) A quantitative ELISA assay for the fragile X mental retardation 1 protein. J Mol Diagn 11:281–289

    PubMed  CAS  Google Scholar 

  163. McConkie-Rosell A, Finucane B, Cronister A, Abrams L, Bennett RL, Pettersen BJ (2005) Genetic counselling for fragile X syndrome: updated recommendations of the NSGC. J Genet Couns 14:249–270

    PubMed  Google Scholar 

  164. Fragile X (1994) syndrome: diagnostic and carrier testing (policy statement). Am J Med Genet 53:380–381

    Google Scholar 

  165. Hall DA, Berry-Kravis E, Hagerman RJ et al (2006) Symptomatic treatment in the fragile X associated tremor/ataxia syndrome. Mov Disord 21:1741–1744

    PubMed  Google Scholar 

  166. Hagerman RJ, Murphy MA, Wittenberger MD (1988) A controlled trial of stimulant medication in children with fragile X syndrome. Am J Med Genet 30:377–392

    PubMed  CAS  Google Scholar 

  167. Torroi MG, Vernacotola S, Mariotti P et al (1999) Double-blind placebo controlled study of L-acetylcarnitine for the treatment of hyperactive behaviour in fragile x syndrome. Am J Med Genet 87:366–368

    Google Scholar 

  168. Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP (2005) Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 49:1053–1066

    PubMed  CAS  Google Scholar 

  169. McBride SM, Choi CH, Wang Y et al (2005) Pharmacological rescue of synaptic plasticity, courtship behaviour, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 45:753–764

    PubMed  CAS  Google Scholar 

  170. Restivo L, Ferrari F, Passimo E et al (2005) Enriched environment promotes behavioural and morphological recovery in a mouse model for the fragile X syndrome. Proc Natl Acad Sci USA 102:11557–11562

    Google Scholar 

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  1. Department of Psychiatry, Clinical Science Institute, National University of Ireland Galway, Galway, Ireland

    Anne Gallagher & Brian Hallahan

  2. Department of Psychiatry, Roscommon County Hospital, Roscommon, Ireland

    Brian Hallahan

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  1. Anne Gallagher
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  2. Brian Hallahan
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Correspondence to Brian Hallahan.

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Gallagher, A., Hallahan, B. Fragile X-associated disorders: a clinical overview. J Neurol 259, 401–413 (2012). https://doi.org/10.1007/s00415-011-6161-3

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