Advertisement

Unstable Mutations in the FMR1 Gene and the Phenotypes

  • Danuta Loesch
  • Randi Hagerman
Part of the Advances in Experimental Medicine and Biology book series (AEMB)

Abstract

Fragile X syndrome (FXS), a severe neurodevelopmental anomaly, and one of the earliest disorders linked to an unstable (‘dynamic’) mutation, is caused by the large (>200) CGG repeat expansions in the noncoding portion of the FMR1 (Fragile X Mental Retardation-1) gene. These expansions, termed full mutations, normally silence this gene’s promoter through methylation, leading to a gross deficit of the Fragile X Mental Retardation Protein (FMRP) that is essential for normal brain development. Rare individuals with the expansion but with an unmethy latedpromoter (and thus, FMRP production), present a much less severe form of FXS.

However, a unique feature of the relationship between the different sizes of CGG expanded tract and phenotypic changes is that smaller expansions (<200) generate a series of different clinical manifestations and/or neuropsychological changes. The major part of this chapter is devoted to those FMR1 alleles with small (55–200) CGG expansions, termed ‘premutations’, which have the potential for generating the full mutation alleles on mother-offspring transmission, on the one hand, and are associated with some phenotypic changes, on the other. Thus, the role of several factors known to determine the rate of CGG expansion in the premutation alleles is discussed first. Then, an account of various neurodevelopmental, cognitive, behavioural and physical changes reported in carriers of these small expansions is given, and possible association of these conditions with a toxicity of the elevated FMR1 gene’s transcript (mRNA) is discussed.

The next two sections are devoted to major and well defined clinical conditions associated with thepremutationalleles. The first oneis the lateonsetneurodegenerative disorder termed fragile X-associated tremor ataxia syndrome (FXTAS). The wide range of clinical and neuropsychological manifestations of this syndrome, and their relevance to elevated levels of the FMR1 mRNA, are described. Another distinct disorder linked to the CGG repeat expansions within the premutation range is fragile X-associated primary ovarian insufficiency (FXPOI) in females, and an account of the spectrum of manifestations of this disorder, together with the latest findings suggesting an early onset of the ovarian changes, is given.

In the following section, the most recent findings concerning the possible contribution of FMR1 ‘grey zone’ alleles (those with the smallest repeat expansions overlapping with the normal range i.e., 41–54 cGGs), to the psychological and clinical manifestations, already associated with premutation alleles, are discussed. Special emphasis has been placed on the possibility that the modest elevation of ‘toxic’ FMR1 mrNa in the carriers of grey zone alleles may present an additional risk for some neurodegenerative diseases, such as those associated with parkinsonism, by synergizing with either other susceptibility genes or environmental poisons.

The present status of the treatment of fragile X-related disorders, especially fXS, is presented in the last section of this chapter. Pharmacological interventions in this syndrome have recently extended beyond stimulants and antipsychotic medications, and the latest trials involving a group of Glur5 antagonists aim to ascertain if these substances have the potential to reverse some of the neurobiological abnormalities of FXS.

Keywords

Premature Ovarian Failure Full Mutation Premutation Carrier Tandem Repeat Polymorphism Grey Zone Allele 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Preview

Unable to display preview. Download preview PDF.

Unable to display preview. Download preview PDF.

References

  1. 1.
    Verkerk AJ, Pieretti M, Sutcliffe JS et al. Identification of a gene (FMR-1) containing a CGG repeat coincident with a breakpoint cluster region exhibiting length variation in fragile X syndrome. Cell 1991; 65(5):905–914.PubMedGoogle Scholar
  2. 2.
    Lubs HA. A marker X chromosome. American Journal of Human Genetics 1969; 21(3):231–244.PubMedGoogle Scholar
  3. 3.
    Cronister A, Schreiner R, Wittenberger M et al. Heterozygous fragile X female: historical, physical, cognitive, and cytogenetic features. Am J Med Genet 1991; 38(2–3):269–274.PubMedGoogle Scholar
  4. 4.
    Sullivan AK, Marcus M, Epstein MP et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005; 20(2):402–412.PubMedGoogle Scholar
  5. 5.
    Wittenberger MD, Hagerman RJ, Sherman SL et al. The FMR1 premutation and reproduction. Fertil Steril 2007; 87(3):456–465.PubMedGoogle Scholar
  6. 6.
    Welt CK. Primary ovarian insufficiency: a more accurate term for premature ovarian failure. Clin Endocrinol (Oxf) 2008; 68(4):499–509.Google Scholar
  7. 7.
    Hagerman RJ, Leehey M, Heinrichs W et al. Intention tremor, parkinsonism, and generalized brain atrophy in male carriers of fragile X. Neurology 2001; 57:127–130.PubMedGoogle Scholar
  8. 8.
    Jacquemont S, Hagerman RJ, Leehey M et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. American Journal of Human Genetics 2003; 72(4):869–878.PubMedGoogle Scholar
  9. 9.
    Berry-Kravis E, Abrams L, Coffey SM et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics and testing guidelines. Mov Disord 2007; 22(14):2018–2030.PubMedGoogle Scholar
  10. 10.
    Tassone F, Berry-Kravis E, eds. Fragile X-associated Tremor Ataxia Syndrome (FXTAS). New York, NY: Springer-Verlag New York Inc.; 2011.Google Scholar
  11. 11.
    Tassone F, Hagerman RJ, Taylor AK et al. Elevated levels of FMR1 mRNA in carrier males: anew mechanism of involvement in the fragile-X syndrome. American Journal of Human Genetics 2000; 66(1):6–15.PubMedGoogle Scholar
  12. 12.
    Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective. American Journal of Human Genetics 2004; 74(5):805–816.PubMedGoogle Scholar
  13. 13.
    Garcia-Arocena D, Hagerman PJ. Advances in understanding the molecular basis of FXTAS. Hum Mol Genet 2010; 19(R1):R83–R89.PubMedGoogle Scholar
  14. 14.
    Farzin F, Perry H, Hessl D et al. Autism spectrum disorders and attention-deficit/hyperactivity disorder in boys with the fragile X premutation. J Dev Behav Pediatr 2006; 27(2 Suppl):S137–S144.PubMedGoogle Scholar
  15. 15.
    Aziz M, Stathopulu E, Callias M et al. Clinical features of boys with fragile X premutations and intermediate alleles. Am J Med Genet, in press 2003; 121B(1):119–127.PubMedGoogle Scholar
  16. 16.
    Clifford S, Dissanayake C, Bui QM et al. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. Journal of Autism and Developmental Disorders 2007; 37(4):738–747.PubMedGoogle Scholar
  17. 17.
    Goodlin-Jones B, Tassone F, Gane LW et al. Autistic spectrum disorder and the fragile X premutation. J Dev Behav Pediatr 2004; 25(6):392–398.PubMedGoogle Scholar
  18. 18.
    Bailey DB Jr., Raspa M, Olmsted M et al. Co-occurring conditions associated with FMR1 gene variations: findings from anationalparent survey. American Journal of Medical Genetics 2008; 146A(16):2060–2069.PubMedGoogle Scholar
  19. 19.
    Roberts JE, Bailey DB Jr., Mankowski J et al. Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(l): 130–139.PubMedGoogle Scholar
  20. 20.
    Hessl D, Tassone F, Loesch DZ et al. Abnormal elevation of FMR1 mRNA is associated with psychological symptoms in individuals with the fragile X premutation. Am J Med Genet B Neuropsychiatr Genet 2005; 139B(1):115–121.PubMedGoogle Scholar
  21. 21.
    Cornish K, Kogan C, Turk J et al. The emerging fragile X premutation phenotype: evidence from the domain of social cognition. Brain and cognition 2005; 57(1):53–60.PubMedGoogle Scholar
  22. 22.
    Rodriguez-Revenga L, Madrigal I, Pagonabarraga J et al. Penetrance of FMR1 premutation associated pathologies in fragile X syndrome families. Eur J Hum Genet 2009; 17(10):1359–1362.PubMedGoogle Scholar
  23. 23.
    Bourgeois JA, Coffey SM, Rivera SM et al. A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 2009; 70(6):852–862.PubMedGoogle Scholar
  24. 24.
    Bourgeois J, Seritan A, Casillas E et al. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry 2010: doi: 10.4088/JCP.4009m05407blu, Published online by Physicians Postgraduate Press, Inc.Google Scholar
  25. 25.
    Grigsby J, Brega AG, Engle K et al. Cognitive profile of fragile X premutation carriers with and without fragile X-associated tremor/ataxia syndrome. Neuropsychology 2008; 22(1):48–60.PubMedGoogle Scholar
  26. 26.
    Hashimoto RI, Backer KC, Tassone F et al. An fMRI study of the prefrontal activity during the performance of a working memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FXTAS). Journal of Psychiatric Research 2010: doi:10.1016/j.jpsychires.2010.1004.1030.Google Scholar
  27. 27.
    Coffey SM, Cook K, Tartaglia N et al. Expanded clinical phenotype of women with the FMRI premutation. American Journal of Medical Genetics 2008; 146A(8):1009–1016.PubMedGoogle Scholar
  28. 28.
    Hagerman RJ. Physical and behavioral phenotype. In: Hagerman RJ, Hagerman PJ, eds. Fragile X syndrome: Diagnosis, Treatment and Research, 3rd edition. Baltimore: The Johns Hopkins University Press; 2002:3–109.Google Scholar
  29. 29.
    Pieretti M, Zhang FP, Fu YH et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell 1991;66(4):817–822.PubMedGoogle Scholar
  30. 30.
    Tassone F, Hagerman RJ, Ikle DN et al. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet 1999; 84(3):250–261.PubMedGoogle Scholar
  31. 31.
    Loesch DZ, Huggins RM, Hagerman RJ. Phenotypic variation and FMRP levels in fragile X. Ment Retard Dev Disabil Res Rev 2004; 10(l):31–41.PubMedGoogle Scholar
  32. 32.
    Comery TA, Harris JB, Willems PJ et al. Abnormal dendritic spines in fragile X knockout mice: maturation and pruning deficits. Proc Natl Acad Sci U S A 1997; 94(10):5401–5404.PubMedGoogle Scholar
  33. 33.
    Devys D, Lutz Y, Rouyer N et al. The FMR-1 protein is cytoplasmic, most abundant in neurons and appears normal in carriers of a fragile X premutation. Nature genetics 1993; 4(4):335–340.PubMedGoogle Scholar
  34. 34.
    Hinds HL, Ashley CT, Sutcliffe JS et al. Tissue specific expression of FMR-1 provides evidence for a functional role in fragile X syndrome. Nat Genet 1993; 3(1):36–43.PubMedGoogle Scholar
  35. 35.
    Irwin SA, Galvez R, Greenough WT. Dendritic spine structural anomalies in fragile-X mental retardation syndrome. Cereb Cortex 2000; 10(10):1038–1044.PubMedGoogle Scholar
  36. 36.
    Witt R, Kaspar B, Brazelton AD et al. Developmental localization of fragile X mRNA in rat brain. Soc Neurosci 1995; 21(1):293–296.Google Scholar
  37. 37.
    Weiler IJ, Greenough WT. Synaptic synthesis of the Fragile X protein: possible involvement in synapse maturation and elimination. Am J Med Genet 1999; 83(4):248–252.PubMedGoogle Scholar
  38. 38.
    Weiler IJ, Irwin SA, Klintsova AY et al. Fragile X mental retardation protein is translated near synapses in response to neurotransmitter activation PNAS 1997; 94(10):5395–5400.Google Scholar
  39. 39.
    Basseil GJ, Warren ST. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 2008; 60(2):201–214.Google Scholar
  40. 40.
    Dolen G, Carpenter RL, Ocain TD et al. Mechanism-based approaches to treating fragile X. Pharmacol Ther 2010; 127(l):78–93.PubMedGoogle Scholar
  41. 41.
    Oostra BA, Willemsen R. FMR1: a gene with three faces. Biochim Biophys Acta 2009; 1790(6):467–477.PubMedGoogle Scholar
  42. 42.
    Qin M, Kang J, Burlin TV et al. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouse. J Neurosci 2005; 25(20):5087–5095.PubMedGoogle Scholar
  43. 43.
    Darnell JC, van Dreische S, Zhang C et al. HITS-CLIP Identifies Specific Neuronal mRNA Targets of Translational Repression by the Fragile X Mental Retardation Protein, FMRP [abstract]. Paper presented at: Keystone Symposia 2010; Snowbird, UT.Google Scholar
  44. 44.
    Hagerman R, Hoem G, Hagerman P. Fragile X and autism: intertwined at the molecular level leading to targeted treatments. Mol Autism 2010; 1(1): 12.PubMedGoogle Scholar
  45. 45.
    Zalfa F, Eleuteri B, Dickson KS et al. A new function for the fragile X mental retardation protein in regulation of PSD-95 mRNA stability. Nat Neurosci 2007; 10(5):578–587.PubMedGoogle Scholar
  46. 46.
    Dahlhaus R, El-Husseini A. Altered neuroligin expression is involved in social deficits in a mouse model of the fragile X syndrome. Behavioural Brain Research 2010; 208(1):96–105.PubMedGoogle Scholar
  47. 47.
    Miyashiro KY, Beckel-Mitchener A, Purk TP et al. RNA cargoes associating with FMRP reveal deficits in cellular functioning in Fmr1 null mice. Neuron 2003; 37(3):417–431.PubMedGoogle Scholar
  48. 48.
    Darnell JC, Mostovetsky O, Darnell RB. FMRP RNA targets: identification and validation. Genes, Brain and Behavior 2005; 4(6):341–349.Google Scholar
  49. 49.
    Sharma A, Hoeffer CA, Takayasu Y et al. Dysregulation of mTOR signaling in fragile X syndrome. J Neurosci 2010; 30(2):694–702.PubMedGoogle Scholar
  50. 50.
    Tassone F. mTOR up-regulation in patients with FXS [abstract]. Paper presented at: FRAXA Investigators meeting 2010; Durham, NH.Google Scholar
  51. 51.
    de Vries PJ. Targeted treatments for cognitive and neurodevelopmental disorders in tuberous sclerosis complex. Neurotherapeutics 2010; 7(3):275–282.PubMedGoogle Scholar
  52. 52.
    Harris SW, Hessl D, Goodlin-Jones B et al. Autism profiles of males with fragile X syndrome. Am J Ment Retard 2008; 113(6):427–438.PubMedGoogle Scholar
  53. 53.
    Hatton DD, Sideris J, Skinner M et al. Autistic behavior in children with fragile X syndrome: prevalence, stability and the impact of FMRP. American Journal of Medical Genetics 2006; 140(17): 1804–1813.Google Scholar
  54. 54.
    Kaufmann WE, Cortell R, Kau AS et al. Autism spectrum disorder in fragile X syndrome: communication, social interaction and specific behaviors. Am J Med Genet 2004; 129A(3):225–234.PubMedGoogle Scholar
  55. 55.
    Cordeiro L, Ballinger E, Hagerman R et al. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. Journal of Neurodevelopmental Disorders, in press.Google Scholar
  56. 56.
    Munir F, Cornish KM, Wilding J. A neuropsychological profile of attention deficits in young males with fragile X syndrome. Neuropsychologia 2000; 38(9):1261–1270.PubMedGoogle Scholar
  57. 57.
    Sullivan K, Hatton D, Hammer J et al. ADHD symptoms in children with FXS. American Journal of Medical Genetics 2006; 140(21):2275–2288.PubMedGoogle Scholar
  58. 58.
    Cornish KM, Turk J, Hagerman R. The fragile X continuum: new advances and perspectives. J Intellect Disabil Res 2008; 52(Pt 6):469–482.PubMedGoogle Scholar
  59. 59.
    Butler MG, Pratesi R, Watson MS et al. Anthropomwetric and craniofacial patterns in mentally retarded males with emphasis on the fragile X syndrome. Clinical genetics 1993; 44(3):129–138.PubMedGoogle Scholar
  60. 60.
    Hagerman RJ, Hull CE, Safanda JF et al. High functioning fragile X males: demonstration of an unmethylated fully expanded FMR-1 mutation associated with protein expression. Am J Med Genet 1994; 51(4):298–308.PubMedGoogle Scholar
  61. 61.
    Wright-Talamante C, Cheema A, Riddle JE et al. A controlled study of longitudinal IQ changes in females and males with fragile X syndrome. Am J Med Genet 1996; 64(2):350–355.PubMedGoogle Scholar
  62. 62.
    Tassone F, Hagerman RJ, Loesch DZ et al. Fragile X males with unmethylated, full mutation trinucleotide repeat expansions have elevated levels of FMR1 messenger RNA. Am J Med Genet 2000; 94(3):232–236.PubMedGoogle Scholar
  63. 63.
    Hall D, Pickler L, Riley K et al. Parkinsonism and cognitive decline in a fragile X mosaic male. Mov Disord 2010; 25(10):1523–1524.PubMedGoogle Scholar
  64. 64.
    Utari A, Adams E, Berry-Kravis E et al. Aging in fragile X syndrome. Journal of Neurodevelopmental Disorders 2010; 2(2):70–76.PubMedGoogle Scholar
  65. 65.
    de Vries BB, Wiegers AM, Smits AP et al. Mental status of females with an FMR1 gene full mutation. American Journal of Human Genetics 1996; 58(5):1025–1032.PubMedGoogle Scholar
  66. 66.
    Bennetto L, Pennington BF. Neuropsychology. In: Hagerman RJ, Hagerman PJ, eds. Fragile X Syndrome: Diagnosis, Treatment and Research.3rd edition. Baltimore: Johns Hopkins University Press; 2002:206–248.Google Scholar
  67. 67.
    Angkustsiri K, Wirojanan J, Deprey LJ et al. Fragile X syndrome with anxiety disorder and exceptional verbal intelligence. American Journal of Medical Genetics 2008; 146(3):376–379.PubMedGoogle Scholar
  68. 68.
    Hagerman RJ, Berry-Kravis E, Kaufmann WE et al. Advances in the treatment of fragile X syndrome. Pediatrics 2009; 123(1):378–390.PubMedGoogle Scholar
  69. 69.
    Epstein J, Riley K, Sobesky W. The treatment of emotional and behavioral problems. In: Hagerman R, Hagerman P, eds. Fragile X Syndrome: Diagnosis, Treatment and Research. 3rd edition. Baltimore: The Johns Hopkins University Press; 2002:339–362.Google Scholar
  70. 70.
    Pembrey ME, Winter RM, Davies KE. A premutation that generates a defect at crossing over explains the inheritance of fragile X mental retardation. Am J Med Genet 1985; 21:709–717.PubMedGoogle Scholar
  71. 71.
    Fu YH, Kuhl DP, Pizzuti A et al. Variation of the CGG repeat at the fragile X site results in genetic instability: resolution of the Sherman paradox. Cell 1991; 67(6):1047–1058.PubMedGoogle Scholar
  72. 72.
    Yu S, Mulley J, Loesch D et al. Fragile-X syndrome: unique genetics of the heritable unstable element. American Journal of Human Genetics 1992; 50(5):968–980.PubMedGoogle Scholar
  73. 73.
    Heitz D, Devys D, Imbert G et al. Inheritance of the fragile X syndrome: size of the fragile X premutation is a major determinant of the transition to full mutation. Journal of Medical Genetics 1992; 29(11):794–801.PubMedGoogle Scholar
  74. 74.
    Snow K, Doud LK, Hagerman R et al. Analysis of a CGG sequence at the FMR-1 locus in fragile X families and in the general population. Am J Hum Genet 1993; 53(6): 1217–1228.PubMedGoogle Scholar
  75. 75.
    Vaisanen ML, Kahkonen M, Leisti J. Diagnosis of fragile X syndrome by direct mutation analysis. Hum Genet 1994; 93(2): 143–147.PubMedGoogle Scholar
  76. 76.
    Nolin SL, Lewis FA 3rd, Ye LL et al. Familial transmission of the FMR1 CGG repeat. American Journal of Human Genetics 1996; 59(6):1252–1261.PubMedGoogle Scholar
  77. 77.
    Ashley-Koch AE, Robinson H, Glicksman AE et al. Examination of factors associated with instability of the FMR1 CGG repeat. Am J Hum Genet 1998; 63(3):776–785.PubMedGoogle Scholar
  78. 78.
    Nolin SL, Brown WT, Glicksman A et al. Expansion of the fragile X CGGrepeat in females with premutation or intermediate alleles. American Journal of Human Genetics 2003; 72:454–464.PubMedGoogle Scholar
  79. 79.
    Brown WT, Houck GE Jr., Jeziorowska A et al. Rapid Fragile X carrier screening and prenatal diagnosis using a nonradioactive PCR test. JAMA 1993; 270(13): 1569–1575.PubMedGoogle Scholar
  80. 80.
    Snow K, Tester DJ, Kruckeberg KE et al. Sequence analysis of the fragile X trinucleotide repeat: implications for the origin of the fragile X mutation. Hum Mol Genet 1994; 3(9):1543–1551.PubMedGoogle Scholar
  81. 81.
    Brown WT, Nolin S, Houck G Jr. et al. Prenatal diagnosis and carrier screening for fragile X by PCR. Am JMedGenet 1996; 64(1):191–195.Google Scholar
  82. 82.
    Youings SA, Murray A, Dennis N et al. FRAXA and FRAXE: the results of a five year survey. J Med Genet 2000; 37(6):415–421.PubMedGoogle Scholar
  83. 83.
    Dombrowski C, Levesque S, Morel ML et al. 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 2002; 11(4):371–378.PubMedGoogle Scholar
  84. 84.
    Mitchell RJ, Holden JJ, Zhang C et al. FMR1 alleles in Tasmania: a screening study of the special educational needs population. Clinical genetics 2005; 67(l):38–46.PubMedGoogle Scholar
  85. 85.
    Zhou Y, Lum JM, Yeo GH et al. Simplified molecular diagnosis of fragile X syndrome by fluorescent methylation-specific PCR and GeneScan analysis. Clin Chem 2006; 52(8):1492–1500.PubMedGoogle Scholar
  86. 86.
    Khaniani MS, Kalitsis P, Burgess T et al. An improved diagnostic PCR assay for identification of cryptic heterozygosity for CGG triplet repeat alleles in the Fragile X Gene (FMR1). Mol Cytogenet 2008; 1(1):5.PubMedGoogle Scholar
  87. 87.
    Filipovic-Sadic S, Sah S, Chen L et al. Anovel FMR1 PCR method for the routine detection of low-abundance expanded alleles and full mutations in fragile X syndrome. Clin Chem 2010; 56(3):399–408.PubMedGoogle Scholar
  88. 88.
    Fernandez-Carvajal I, Lopez Posadas B, Pan R et al. Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J Mol Diagn 2009; 11(4):306–310.PubMedGoogle Scholar
  89. 89.
    Sullivan AK, Crawford DC, Scott EH et al. Paternally transmitted FMR1 alleles are less stable than maternally transmitted alleles in the common and intermediate size range. Am J Hum Genet 2002; 70(6): 1532–1544.PubMedGoogle Scholar
  90. 90.
    Maddalena A, Richards CS, McGinniss MJ et al. Technical standards and guidelines for fragile X: the first of a series of disease-specific supplements to the Standards and Guidelines for Clinical Genetics Laboratories of the American College of Medical Genetics. Quality Assurance Subcommittee of the Laboratory Practice Committee. Genet Med 2001; 3(3):200–205.Google Scholar
  91. 91.
    Loesch DZ, Huggins R, Petrovic V et al. Expansion of the CGG repeat in fragile X in the FMR1 gene depends on the sex of the offspring. American Journal of Human Genetics 1995; 57(6): 1408–1413.PubMedGoogle Scholar
  92. 92.
    Huggins RM, Loesch DZ, Qian GQ et al. Hierarchical Bayes model for random haplotype and family effects in the transmission of fragile-X. Genet Epidemiol 2004; 26(4):294–304.PubMedGoogle Scholar
  93. 93.
    Ashley AE, Sherman SL. Population dynamics of a meiotic/mitotic expansion model for the fragile X syndrome. Am J Hum Genet 1995; 57(6):1414–1425.PubMedGoogle Scholar
  94. 94.
    Zhong N, Ju W, Pietrofesa J et al. Fragile X “gray zone” alleles: AGG patterns, expansion risks and associated haplotypes. Am J Med Genet 1996; 64(2):261–265.PubMedGoogle Scholar
  95. 95.
    Eichler EE, Holden JJ, Popovich BW et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nature genetics 1994; 8(l):88–94.PubMedGoogle Scholar
  96. 96.
    Eichler EE, Macpherson JN, Murray A et al. Haplotype and interspersion analysis of the FMR1 CGG repeat identifies two different mutational pathways for the origin of the fragile X syndrome. Hum Mol Genet 1996; 5(3):319–330.PubMedGoogle Scholar
  97. 97.
    Eichler EE, Nelson DL. Genetic variation and evolutionary stability of the FMR1 CGG repeat in six closed human populations. Am J Med Genet 1996; 64(l):220–225.PubMedGoogle Scholar
  98. 98.
    Zhong N, Yang W, Dobkin C et al. Fragile X gene instability: anchoring AGGs and linked microsatellites. Am J Hum Genet 1995; 57(2):351–361.PubMedGoogle Scholar
  99. 99.
    Yrigollen C, Long K, Tong T et al. The role of AGG interruptions in the stability of FMR1 gene. Paper presented at: 12th International Fragile X Conference; 2010; Detroit, MI.Google Scholar
  100. 100.
    Richards RI, Holman K, Kozman H et al. Fragile X syndrome: genetic localisation by linkage mapping of two microsatellite repeats FRAXAC1 and FRAXAC2 which immediately flank the fragile site. J Med Genet 1991; 28(12):818–823.PubMedGoogle Scholar
  101. 101.
    Zhong N, Kajanoja E, Smits B et al. Fragile X founder effects and new mutations in Finland. Am J Med Genet 1996a; 64(1):226–233.PubMedGoogle Scholar
  102. 102.
    Faradz SMH, Pattiiha MZ, Leigh DA et al. Genetic diversity at the FMR1 locus in the Indonesian population. Annals of Human Genetics 2000; 64(4):329–339.PubMedGoogle Scholar
  103. 103.
    Kunst CB, Warren ST. Cryptic and polar variation of the fragile X repeat could result in predisposing normal alleles. Cell 1994; 77(6):853–861.PubMedGoogle Scholar
  104. 104.
    Gunter C, Paradee W, Crawford DC et al. Re-examination of factors associated with expansion of CGG repeats using a single nucleotide polymorphism in FMR1. Hum Mol Genet 1998; 7(12):1935–1946.PubMedGoogle Scholar
  105. 105.
    Brightwell G, Wycherley R, Waghorn A. SNP genotypingusing asimple and rapid single-tube modification of ARMS illustrated by analysis of 6 SNPs in a population of males with FRAXA repeat expansions. Molecular and Cellular Probes 2002; 16(4):297–305.PubMedGoogle Scholar
  106. 106.
    Curlis Y, Zhang C, Holden JJ et al. Haplotype study of intermediate-length alleles at the fragile X (FMR1) gene: ATL1, FMRb and microsatellite haplotypes differ from those found in common-size FMR1 alleles. Hum Biol 2005; 77(1):137–151.PubMedGoogle Scholar
  107. 107.
    Toledano-Alhadef H, Basel-Vanagaite L, Magal N et al. Fragile-X carrier screening and the prevalence of premutation and full-mutation carriers in Israel. Am J Hum Genet 2001; 69(2):351–360.PubMedGoogle Scholar
  108. 108.
    Dawson AJ, Chodirker BN, Chudley AE. Frequency of FMR1 premutations in a consecutive newborn population by PCR screening of Guthrie blood spots. Biochem Mol Med 1995; 56(1):63–69.PubMedGoogle Scholar
  109. 109.
    Rousseau F, Rouillard P, Morel ML et al. Prevalence of carriers of premutation-size alleles of the FMRI gene — and implications for the population genetics of the fragile X syndrome. American Journal of Human Genetics 1995; 57(5):1006–1018.PubMedGoogle Scholar
  110. 110.
    Hagerman PJ. The fragile X prevalence paradox. Journal of Medical Genetics 2008; 45(8):498–499.PubMedGoogle Scholar
  111. 111.
    Fernandez-Carvajal I, Walichiewicz P, Xiaosen X et al. Screening for expanded alleles of the FMRI gene in blood spots from newborn males in a Spanish population. J Mol Diagn 2009; 11(4):324–329.PubMedGoogle Scholar
  112. 112.
    Song FJ, Barton P, Sleightholme V et al. Screening for fragile X syndrome: a literature review and modelling study. Health Technol Assess 2003; 7(16):l–106.Google Scholar
  113. 113.
    Otsuka S, Sakamoto Y, Siomi H et al. Fragile X carrier screening and FMRI allele distribution in the Japanese population. Brain and Development 2010; 32(2): 110–114.PubMedGoogle Scholar
  114. 114.
    Loesch DZ, Huggins R, Hay DA et al. Genotype-phenotype relationships in fragile X syndrome: a family study. American Journal of Human Genetics 1993; 53(5):1064–1073.PubMedGoogle Scholar
  115. 115.
    Hagerman RJ, Staley LW, O’Conner R et al. Learning-disabled males with a fragile X CGG expansion in the upper premutation size range. Pediatrics 1996; 97(1): 122–126.PubMedGoogle Scholar
  116. 116.
    Loesch D, Hay D, Mulley J. Transmitting males and carrier females in fragile X-revisited. Am J Med Genet 1994; 51(4):392–399.PubMedGoogle Scholar
  117. 117.
    Hull C, Hagerman RJ. A study of the physical, behavioral and medical phenotype, including anthropometric measures, of females with fragile X syndrome. Am J Dis Child 1993; 147(11): 1236–1241.PubMedGoogle Scholar
  118. 118.
    Riddle JE, Cheema A, Sobesky WE et al. Phenotypic involvement in females with the FMR1 gene mutation. Am J Ment Retard 1998; 102(6):590–601.PubMedGoogle Scholar
  119. 119.
    Loesch DZ, Huggins RM, Bui QM et al. Effect of fragile X status categories and FMRP deficits on cognitive profiles estimated by robust pedigree analysis. Am J Med Genet A 2003; 122A(1): 13–23.PubMedGoogle Scholar
  120. 120.
    Loesch DZ, Bui QM, Grigsby J et al. Effect of the fragile X status categories and the fragile X mental retardation protein levels on executive functioning in males and females with fragile X. Neuropsychology 2003; 17(4):646–657.PubMedGoogle Scholar
  121. 121.
    Grigsby J, Kaye K. Behavioral Dyscontrol Scale: Manual. 2nd edition. 1996.Google Scholar
  122. 122.
    Meyers JE, Meyers KR. Rey Complex Figure Test and Recognition Trial Manual. Odessa FI.: Psychological Assessment Resources, Inc.; 1995.Google Scholar
  123. 123.
    Moore CJ, Daly EM, Schmitz N et al. A neuropsychological investigation of male premutation carriers of fragile X syndrome. Neuropsychologia 2004; 42(14):1934–1947.PubMedGoogle Scholar
  124. 124.
    Lachiewicz AM, Dawson DV, Spiridigliozzi GA et al. Arithmetic difficulties in females with the fragile X premutation. American Journal of Medical Genetics 2006; 140(7):665–672.PubMedGoogle Scholar
  125. 125.
    Keri S, Benedek G. Visual pathway deficit infernale fragile X premutation carriers: apotentialendophenotype. Brain Cogn 2009; 69(2):291–295.PubMedGoogle Scholar
  126. 126.
    Keri S, Benedek G. The perception of biological and mechanical motion in female fragile X premutation carriers. Brain Cogn 2010; 72(2):197–201.PubMedGoogle Scholar
  127. 127.
    Hunsaker MR, Goodrich-Hunsaker NJ, Willemsen R et al. Temporal ordering deficits in female CGG KI mice heterozygous for the fragile X premutation. Behavioural Brain Research 2010; 213(2):263–268.PubMedGoogle Scholar
  128. 128.
    Minguez M, Ibáñez B, Ribate MP et al. Risk of cognitive impairment in female premutation carriers of fragile X premutation: analysis by means of robust segmented linear regression models. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(2):262–270.PubMedGoogle Scholar
  129. 129.
    Goodlin-Jones BL, Tassone F, Gane LW et al. Autistic spectrum disorder and the fragile X premutation. J Dev Behav Pediatr 2004; 25(6):392–398.PubMedGoogle Scholar
  130. 130.
    Loesch DZ, Huggins RM, Bui QM et al. Relationship of deficits of FMR1 gene specific protein with physical phenotype of fragile X males and females in pedigrees: a new perspective. Am J Med Genet A 2003; 118A(2):127–134.PubMedGoogle Scholar
  131. 131.
    Jakala P, Hanninen T, Ryynanen M et al. Fragile-X: neuropsychological test performance, CGG triplet repeat lengths and hippocampal volumes. J Clin Invest 1997; 100(2):331–338.PubMedGoogle Scholar
  132. 132.
    Murphy DGM, Mentis MJ, Pietrini P et al. Premutation female carriers of fragile X syndrome: a pilot study on brain anatomy and metabolism. Journal of the American Academy of Child and Adolescent Psychiatry 1999; 38(10):1294–1301.PubMedGoogle Scholar
  133. 133.
    Moore CJ, Daly EM, Tassone F et al. The effect of premutation of X chromosome CGG trinucleotide repeats on brain anatomy. Brain 2004; 127(Pt 12):2672–2681.PubMedGoogle Scholar
  134. 134.
    Adams PE, Adams JS, Nguyen DV et al. Psychological symptoms correlate with reduced hippocampal volume in fragile X premutation carriers. Am J Med Genet B Neuropsychiatr Genet 2010; 153B(3); 775–78.PubMedGoogle Scholar
  135. 135.
    Hessl D, Rivera S, Koldewyn K et al. Amygdala dysfunction in men with the fragile X premutation. Brain 2007; 130(2):404–416.PubMedGoogle Scholar
  136. 136.
    Koldewyn K, Hessl D, Adams J et al. Reduced hippocampal activation during recall is associated with elevated FMR1 mRNA and psychiatric symptoms in men with the fragile X premutation. Brain Imaging Behav 2008; 2(2): 105–116.PubMedGoogle Scholar
  137. 137.
    Hagerman RJ, Hagerman PJ. The fragile X premutation: into the phenotypic fold. Current Opinion in Genetics and Development 2002; 12:278–283.PubMedGoogle Scholar
  138. 138.
    Cornish KM, Li L, Kogan CS et al. Age-dependent cognitive changes in carriers of the fragile X syndrome. Cortex 2008; 44(6):628–636.PubMedGoogle Scholar
  139. 139.
    Kogan C, Turk J, Hagerman RJ et al. Impact of the fragile X mental retardation 1 (FMR1) gene premutation on neuropsychiatric functioning in adult males without fragile X-associated tremor/ataxia syndrome: a controlled study. Am J Med Genet B Neuropsychiatr Genet 2008; 147B(6):859–872.PubMedGoogle Scholar
  140. 140.
    Cornish KM, Kogan CS, Li L et al. Lifespan changes in working memory in fragile X premutation males. Brain and Cognition 2009; 69(3):551–558.PubMedGoogle Scholar
  141. 141.
    Sevin M, Kutalik Z, Bergman S et al. Penetrance of marked cognitive impairment in older male carriers of the FMR1 gene premutation. Journal of Medical Genetics 2009; 46(12):818–824.PubMedGoogle Scholar
  142. 142.
    Hunter J, Abramowitz A, Rusin M et al. Is there evidence for neuropsychological and neurobehavioral phenotypes among adults without FXTAS who carry the FMR1 premutation? A review of current literature. Genet Med 2009; 11(2):79–89.PubMedGoogle Scholar
  143. 143.
    Reiss AL, Freund L, Abrams MT et al. Neurobehavioral effects of the fragile X premutation in adult women: a controlled study. American journal of human genetics 1993; 52(5):884–894.PubMedGoogle Scholar
  144. 144.
    Franke P, Leboyer M, Gänsicke M et al. Genotype-phenotype relationship in female carriers of the premutation and full mutation of FMR-1. Psychiatry Research 1998; 80(2):113–127.PubMedGoogle Scholar
  145. 145.
    Al-Semaan Y, Malla AK, Lazosky A. Schizoaffective disorder in a fragile-X carrier. Australian and New Zealand Journal of Psychiatry 1999; 33(3):436–440.PubMedGoogle Scholar
  146. 146.
    Rodriguez-Revenga L, Madrigal I, Alegret M et al. Evidence of depressive symptoms in fragile-X syndrome premutated females. Psychiatr Genet 2008; 18(4): 153–155.PubMedGoogle Scholar
  147. 147.
    Roberts J, Bailey D Jr., Mankowski J et al. Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet B Neuropsychiatr Genet 2009; 150B(1): 130–139.PubMedGoogle Scholar
  148. 148.
    Bailey DJ, Raspa M, Olmsted M et al. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A 2008; 146A(16):2060–2069.PubMedGoogle Scholar
  149. 149.
    Hunter J, Allen E, Abramowitz A et al. Investigation of phenotypes associated with mood and anxiety among male and female fragile X premutation carriers. Behavior Genetics 2008; 38(5):493–502.PubMedGoogle Scholar
  150. 150.
    Allen EG, He W, Yadav-Shah M et al. A study of the distributional characteristics of FMR1 transcript levels in 238 individuals. Hum Genet 2004; 114(5):439–447.PubMedGoogle Scholar
  151. 151.
    Tassone F, Iwahashi C, Hagerman P J. FMR1RNA within the intranuclear inclusions of fragile X-associated tremor/ataxia syndrome (FXTAS). RNA Biol 2004; l(2):103–105.Google Scholar
  152. 152.
    Tassone F, Hagerman RJ, Chamberlain WD et al. Transcription of the FMR1 gene in individuals with fragile X syndrome. Am J Med Genet Fall 2000; 97(3): 195–203.Google Scholar
  153. 153.
    Tassone F, Hagerman R, Taylor A et al. Clinical involvement and protein expression in individuals with the FMR1 premutation. American Journal of Medical Genetics 2000; 91(2):144–152.PubMedGoogle Scholar
  154. 154.
    Tassone F, Hagerman RJ, Garcia-Arocena D et al. Intranuclear inclusions in neural cells with premutation alleles in fragile X associated tremor/ataxia syndrome. Journal of Medical Genetics 2004; 41(4):e43.PubMedGoogle Scholar
  155. 155.
    Kenneson A, Zhang F, Hagedorn CH et al. Reduced FMRP and increased FMR1 transcription is proportionally associated with CGG repeat number in intermediate-length and premutation carriers. Hum Mol Genet 2001; 10(14):1449–1454.PubMedGoogle Scholar
  156. 156.
    Chen LS, Tassone F, Sahota P et al. The (CGG)n repeat element within the 5′ untranslated region of the FMR1 message provides both positive and negative cis effects on in vivo translation of a downstream reporter. Hum Mol Genet 2003; 12(23):3067–3074.PubMedGoogle Scholar
  157. 157.
    Tassone F, Beilina A, Carosi C et al. Elevated FMR1 mRNA in premutation carriers is due to increased transcription. RNA 2007; 13(4):555–562.PubMedGoogle Scholar
  158. 158.
    García-Alegría E, Berta Ibáñez, Mónica Mínguez et al. Analysis of FMR1 gene expression in female premutation carriers using robust segmented linear regression models. RNA 2007; 13:756–762.PubMedGoogle Scholar
  159. 159.
    Şenturk D, Nguyen DV, Tassone F et al. Covariate adjusted correlation analysis with application to FMR1 premutation female carrier data. Biometrics 2009; 65(3):781–792.PubMedGoogle Scholar
  160. 160.
    Hagerman R, Greco CM, Chudley AE et al. Neuropathology and neurodegenerative features in some older male premutation carriers of fragile X syndrome. Am J Hum Genet 2001; 69(177).Google Scholar
  161. 161.
    Hagerman RJ, Hagerman PJ. Fragile X Syndrome and fragile X-associated tremor/ataxia syndrome. In: Robert D. Wells, Ashizawa T, eds. Genetic Instabilities and Neurological Diseases. 2nd edition. Houston, USA: Academic Press; 2006:165–174.Google Scholar
  162. 162.
    Berry-Kravis E, Lewin F, Wuu J et al. Tremor and ataxia in fragile X premutation carriers: blinded videotape study. Ann Neurol 2003; 53(5):616–623.PubMedGoogle Scholar
  163. 163.
    Leehey MA, Berry-Kravis E, Min SJ et al. Progression of tremor and ataxia in male carriers of the FMR1 premutation. Mov Disord 2007; 22(2):203–206.PubMedGoogle Scholar
  164. 164.
    Leehey MA, Hagerman RJ, Landau WM et al. Tremor/ataxia syndrome in fragile X carrier males. Movement Disorders 2002; 17(4):744–745.Google Scholar
  165. 165.
    Jacquemont S, Hagerman RJ, Leehey MA et al. Penetrance of the fragile X-associated tremor/ataxia syndrome in a premutation carrier population. JAMA 2004; 291(4):460–469.PubMedGoogle Scholar
  166. 166.
    Loesch DZ, Churchyard A, Brotchie P et al. Evidence for and a spectrum of, neurological involvement in carriers of the fragile X premutation: FXTAS and beyond. Clinical Genetics 2005; 67(5):412–417.PubMedGoogle Scholar
  167. 167.
    Pugliese P, Annesi G, Cutuli N et al. The fragile X premutation presenting as postprandial hypotension. Neurology 2004; 63(11):2188–2189.PubMedGoogle Scholar
  168. 168.
    Soontarapornchai K, Maselli R, Fenton-Farrell G et al. Abnormal nerve conduction features in fragile X premutation carriers. Archives of Neurology 2008; 65(4):495–498.PubMedGoogle Scholar
  169. 169.
    Adams JS, Adams PE, Nguyen D et al. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 2007; 69(9):851–859.PubMedGoogle Scholar
  170. 170.
    Brunberg JA, Jacquemont S, Hagerman RJ et al. Fragile X premutation carriers: characteristic MR imaging findings of adult male patients with progressive cerebellar and cognitive dysfunction. Am J Neuroradiol 2002;23(10):1757–1766.PubMedGoogle Scholar
  171. 171.
    Moris G, Arias M, López MV, Álvarez V. Hyperintensity in the basis pontis: atypical neuroradiological findings in a woman with FXTAS. Movement Disorders 2010; 25(5):649–650.PubMedGoogle Scholar
  172. 172.
    Loesch DZ, Kotschet K, Trost, NC et al. White matter changes in basic pontis in small expansion FMR1 allele carriers with parkinsonism. Neuropsychiatric Genetics 2011; in press.Google Scholar
  173. 173.
    Greco CM, Berman RF, Martin RM et al. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 2006; 129(Pt 1):243–255.PubMedGoogle Scholar
  174. 174.
    Cohen S, Masyn K, Adams J et al. Molecular and imaging correlates of the fragile X-associated tremor/ ataxia syndrome. Neurology 2006; 67(8):1426–1431.PubMedGoogle Scholar
  175. 175.
    Loesch DZ, Litewka L, Brotchie P et al. Magnetic resonance imaging study in older fragile X premutation male carriers. Annals of Neurology 2005; 58(2):326–330.PubMedGoogle Scholar
  176. 176.
    Greco CM, Hagerman RJ, Tassone F et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain 2002; 125(8): 1760–1771.PubMedGoogle Scholar
  177. 177.
    Willemsen R, Hoogeveen-Westerveld M, Reis S et al. The FMR1 CGG repeat mouse displays ubiquitin-positive intranuclearneuronal inclusions; implications forthe cerebellartremor/ataxiasyndrome. Hum Mol Genet 2003; 12(9):949–959.PubMedGoogle Scholar
  178. 178.
    Wenzel HJ, Hunsaker MR, Greco CM et al. Ubiquitin-positive intranuclear inclusions in neuronal and glial cells in a mouse model of the fragile X premutation. Brain Res 2010; 1318:155–166.PubMedGoogle Scholar
  179. 179.
    Grigsby J, Brega AG, Jacquemont S et al. Impairment in the cognitive functioning of men with fragile X-associated tremor/ataxia syndrome (FXTAS). J Neurol Sci 2006; 248(1–2):227–233.PubMedGoogle Scholar
  180. 180.
    Grigsby J, Brega AG, Leehey MA et al. Impairment of executive cognitive functioning in males with fragile X-associated tremor/ataxia syndrome. Mov Disord 2007; 22(5):645–650.PubMedGoogle Scholar
  181. 181.
    Bacalman S, Farzin F, Bourgeois JA et al. Psychiatric phenotype of the fragile X-associated tremor/ ataxia syndrome (FXTAS) in males: newly described fronto-subcortical dementia. J Clin Psychiatry 2006;67(l):87–94.PubMedGoogle Scholar
  182. 182.
    Bourgeois JA, Cogswell JB, Hessl D et al. Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome. Gen Hosp Psychiatry 2007; 29(4):349–356.PubMedGoogle Scholar
  183. 183.
    Seritan AL, Nguyen DV, Farias ST et al. Dementia in fragile X-associated tremor/ataxia syndrome (FXTAS): comparison with Alzheimer’s disease. Am J Med Genet B Neuropsychiatr Genet 2008; 147B(7):1138–1144.PubMedGoogle Scholar
  184. 184.
    Loesch DZ, Cook M, Litewka L et al. A low symptomatic form of neurodegeneration in younger carriers of the FMR1 premutation, manifesting typical radiological changes. Journal of Medical Genetics 2008; 45(3):179–181.PubMedGoogle Scholar
  185. 185.
    Loesch DZ, Litewka L, Churchyard A et al. Tremor/ataxia syndrome and fragile X premutation: diagnostic caveats. J Clin Neurosci 2007; 14(3):245–248.PubMedGoogle Scholar
  186. 186.
    Capelli LP, Goncalves MR, Kok F et al. Fragile X-associated tremor/ataxia syndrome: intrafamilial variability and the size of the FMR1 premutation CGG repeat. Mov Disord 2007; 22(6):866–870.PubMedGoogle Scholar
  187. 187.
    Greco CM, Tassone F, Garcia-Arocena D et al. Clinical and neuropathologic findings in a woman with the FMR1 premutation and multiple sclerosis. Archives of Neurology 2008; 65(8): 1114–1116.PubMedGoogle Scholar
  188. 188.
    Zhang L, Coffey S, Lua LL et al. FMR1 premutation in females diagnosed with multiple sclerosis. JNeurol Neurosurg Psychiatry 2009; 80(7):812–814.Google Scholar
  189. 189.
    Mothersead PK, Conrad K, Hagerman RJ et al. GRAND ROUNDS: an atypical progressive dementia in a male carrier of the fragile X premutation: an example of fragile X-associated tremor/ataxia syndrome. Appl Neuropsychol 2005; 12(3):169–178.PubMedGoogle Scholar
  190. 190.
    Yachnis AT, Roth HL, Heilman KM. Fragile X Dementia Parkinsonism Syndrome (FXDPS). Cognitive and Behavioral Neurology 2010; 23(l):39–43.doi: 10.1097/WNN.1090b1013e3181bl096e1091b1099.PubMedGoogle Scholar
  191. 191.
    Chonchaiya W, Nguyen DV, Au J et al. Clinical involvement in daughters of men with fragile X-associated tremor ataxia syndrome. Clinical Genetics 2010; 78(1):39–46.Google Scholar
  192. 192.
    Brouwer JR, Huizer K, Severijnen LA et al. CGG-repeat length and neuropathological and molecular correlates in a mouse model for fragile X-associated tremor/ataxia syndrome. J Neurochem 2008; 107(6):1671–1682.PubMedGoogle Scholar
  193. 193.
    Tassone F, Adams J, Berry-Kravis EM et al. CGG repeat length correlates with age of onset of motor signs of the fragile X-associated tremor/ataxia syndrome (FXTAS). Am J Med Genet B Neuropsychiatr Genet 2007; 144(4):566–569.Google Scholar
  194. 194.
    Leehey MA, Berry-Kravis E, Goetz CG et al. FMR1 CGG repeat length predicts motor dysfunction in premutation carriers. Neurology 2008; 70(16 Pt 2):1397–1402.PubMedGoogle Scholar
  195. 195.
    Berry-Kravis E, Goetz CG, Leehey MA et al. Neuropathic features in fragile X premutation carriers. Am J Med Genet A 2007; 143(1): 19–26.PubMedGoogle Scholar
  196. 196.
    Tassone F, Hagerman RJ, Gane LW et al. Strong similarities of the FMR1 mutation in multiple tissues: postmortem studies of a male with a full mutation and a male carrier of a premutation. American Journal of Medical Genetics 1999; 84(3):240–244.PubMedGoogle Scholar
  197. 197.
    Milunsky JM, Malier TA. Fragile X carrier screening and spinocerebellar ataxia in older males. American Journal of Medical Genetics 2004; 125(3):320.Google Scholar
  198. 198.
    Macpherson J, Waghorn A, Hammans S et al. Observation of an excess of fragile-X premutations in a population of males referred with spinocerebellar ataxia. Hum Genet 2003; 112(5–6):619–620.PubMedGoogle Scholar
  199. 199.
    Van Esch H, Dom R, Bex D et al. Screening for FMR-1 premutations in 122 older Flemish males presenting with ataxia. Eur J Hum Genet 2005; 13(1):121–123.PubMedGoogle Scholar
  200. 200.
    Tan EK, Zhao Y, Puong KY et al. Fragile X premutation alleles in SCA, ET and parkinsonism in an Asian cohort. Neurology 2004; 63(2):362–363.PubMedGoogle Scholar
  201. 201.
    Brussino A, Gellera C, Saluto A et al. FMR1 gene premutation is a frequent genetic cause of late-onset sporadic cerebellar ataxia. Neurology 2005; 64(1):145–147.PubMedGoogle Scholar
  202. 202.
    Garcia Arocena D, Louis ED, Tassone F et al. Screen for expanded FMR1 alleles in patients with essential tremor. Mov Disord 2004; 19(8):930–933.PubMedGoogle Scholar
  203. 203.
    Deng H, Le W, Jankovic J. Premutation alleles associated with Parkinson disease and essential tremor. Jama 2004; 292(14):1685–1686.PubMedGoogle Scholar
  204. 204.
    Kamm C, Healy DG, Quinn NP et al. The fragile X tremor ataxia syndrome in the differential diagnosis of multiple system atrophy: data from the EMSA Study Group. Brain 2005; 128(Pt 8): 1855–1860.PubMedGoogle Scholar
  205. 205.
    Toft M, Aasly J, Bisceglio G et al. Parkinsonism, FXTAS and FMR1 premutations. Mov Disord 2005; 20(2):230–233.PubMedGoogle Scholar
  206. 206.
    Zuhlke C, Budnik A, Gehlken U et al. FMR1 premutation as a rare cause of late onset ataxia — evidence for FXTAS in female carriers. J Neurol 2004; 251(11):1418–1419.PubMedGoogle Scholar
  207. 207.
    Garland EM, Vnencak-Jones CL, Biaggioni I et al. Fragile X gene premutation in multiple system atrophy. JNeurol Sci 2004; 227(1):115–118.Google Scholar
  208. 208.
    Biancalana V, Toft M, Le Ber I et al. FMR1 premutations associated with fragile X-associated tremor/ ataxia syndrome in multiple system atrophy. Archives of Neurology 2005; 62(6):962–966.PubMedGoogle Scholar
  209. 209.
    Scixas AI, Maurer MH, Lin M et al. FXTAS, SCA10 and SCA17 in American patients with movement disorders. American Journal of Medical Genetics 2005; 136(l):87–89.Google Scholar
  210. 210.
    Tan EK, Zhao Y, Puong KY et al. Expanded FMR1 alleles are rare in idiopathic Parkinson’s disease. Neurogenetics 2005; 6(1):51–52.PubMedGoogle Scholar
  211. 211.
    Jacquemont S, Farzin F, Hall D et al. Aging in individuals with the FMR1 mutation. Am J Ment Retard 2004; 109(2):154–164.PubMedGoogle Scholar
  212. 212.
    Kurz MW, Schlitter AM, Klenk Y et al. FMR1 alleles in Parkinson’s disease: relation to cognitive decline and hallucinations, a longitudinal study. J Geriatr Psychiatry Neurol 2007; 20(2):89–92.PubMedGoogle Scholar
  213. 213.
    Kraff J, Tang HT, Cilia R et al. Screen for excess FMR1 premutation alleles amongmales with parkinsonism. Arch Neurol 2007; 64(7):1002–1006.PubMedGoogle Scholar
  214. 214.
    Loesch DZ, Khaniani MS, Slater HR et al. Small CGG repeat expansion alleles of FMR 1 gene are associated with parkinsonism. Clinical Genetics 2009; 76(5):471–476.PubMedGoogle Scholar
  215. 215.
    Karmon Y, Gadoth N. Fragile X associated tremor/ataxia syndrome (FXTAS) with dementia in a female harbouring FMR1 premutation. J Neurol Neurosurg Psychiatry 2008; 79(6):738–739.PubMedGoogle Scholar
  216. 216.
    Hagerman RJ, Leavitt BR, Farzin F et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. American Journal of Human Genetics 2004; 74(5):1051–1056.PubMedGoogle Scholar
  217. 217.
    Berry-Kravis E, Potanos K, Weinberg D et al. Fragile X-associated tremor/ataxia syndrome in sisters related to X-inactivation. Annals of Neurology 2005; 57(1):144–147.PubMedGoogle Scholar
  218. 218.
    Jacquemont S, Orrico A, Galli L et al. Spastic paraparesis, cerebellar ataxia and intention tremor: a severe variant of FXTAS? Journal of Medical Genetics 2005; 42(2):el4.Google Scholar
  219. 219.
    O’Dwyer JP, Clabby C, Crown J et al. Fragile X-associated tremor/ataxia syndrome presenting in a woman after chemotherapy. Neurology 2005; 65(2):331–332.Google Scholar
  220. 220.
    Al-Hinti JT, Nagan N, Harik SI. Fragile X premutation in a woman with cognitive impairment, tremor and history of premature ovarian failure. Alzheimer Dis Assoc Disord 2007; 21(3):262–264.PubMedGoogle Scholar
  221. 221.
    Galvao R, Mendes-Soares L, Camara J et al. Triplet repeats, RNA secondary structure and toxic gain-of-function models for pathogenesis. Brain Res Bull 2001; 56(3–4):191–201.PubMedGoogle Scholar
  222. 222.
    Finsterer J. Myotonic dystrophy type 2. European Journal of Neurology 2002; 9(5):441–447.PubMedGoogle Scholar
  223. 223.
    Mankodi A, Thornton CA. Myotonie syndromes. Current Opinion in Neurology 2002; 15(5):545–552.PubMedGoogle Scholar
  224. 224.
    Khalili K, Del Valle L, Muralidharan V et al. Puralpha is essential for postnatal brain development and developmentally coupled cellular proliferation as revealed by genetic inactivation in the mouse. Mol Cell Biol 2003; 23(19):6857–6875.PubMedGoogle Scholar
  225. 225.
    Jin P, Duan R, Qurashi A et al. Pur alpha binds to rCGG repeats and modulates repeat-mediated neurodegeneration in a Drosophila model of fragile X tremor/ataxia syndrome. Neuron2007;55(4):556–564.PubMedGoogle Scholar
  226. 226.
    Garcia-Arocena D, Yang JE, Brouwer JR et al. Fibroblast phenotype inmale carriers of FMR1 premutation alleles. Hum Mol Genet 2010; 19(2):299–312.PubMedGoogle Scholar
  227. 227.
    Paul R, Pessah IN, Gane L et al. Early onset of neurological symptoms in fragile X premutation carriers exposed to neurotoxins. Neurotoxicology 2010; 31(4):399–402.PubMedGoogle Scholar
  228. 228.
    Iwahashi CK, Yasui DH, An HJ et al. Protein composition of the intranuclear inclusions of FXTAS. Brain 2006; 129(Pt 1):256–271.PubMedGoogle Scholar
  229. 229.
    Arocena DG, Iwahashi CK, Won N et al. Induction of inclusion formation and disruption of lamin A/C structure by premutation CGG-repeat RNA in human cultured neural cells. Hum Mol Genet 2005; 14(23):3661–3671.PubMedGoogle Scholar
  230. 230.
    Sellier C, Rau F, Liu Y et al. Sam68 sequestration and partial loss of function are associated with splicing alterations in FXTAS patients. The EMBO Journal 2010; 29(7):1248–1261.PubMedGoogle Scholar
  231. 231.
    Sellier C, Hagerman P, Willemsen R et al. DROSHA/DGCR8 sequestration by expanded CGG repeats leads to global micro-RNA processing alteration in FXTAS patients [abstract]. Paper presented at: 12th International Fragile X Conference; 2010; Detroit, MI.Google Scholar
  232. 232.
    Jin P, Zarnescu DC, Zhang F et al. RNA-mediated neurodegeneration caused by the fragile X premutation rCGG repeats in Drosophila. Neuron 2003; 39(5):739–747.PubMedGoogle Scholar
  233. 233.
    Van Dam D, Errijgers V, Kooy RF et al. Cognitive decline, neuromotor and behavioural disturbances in a mouse model for fragile-X-associated tremor/ataxia syndrome (FXTAS). Behavioural Brain Research 2005; 162(2):233–239.PubMedGoogle Scholar
  234. 234.
    Hashem V, Galloway JN, Mori M et al. Ectopic expression of CGG containing mRNA is neurotoxic in mammals. Hum Mol Genet 2009; 18(13):2443–2451.PubMedGoogle Scholar
  235. 235.
    Greco CM, Soontrapornchai K, Wirojanan J et al. Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome. The Journal of Urology 2007; 177(4): 1434–1437.PubMedGoogle Scholar
  236. 236.
    Brouwer JR, Severijnen E, de Jong FH et al. Altered hypothalamus-pituitary-adrenal gland axis regulation in the expanded CGG-repeat mouse model for fragile X-associated tremor/ataxia syndrome. Psychoneuroendocrinology 2008; 33(6):863–873.PubMedGoogle Scholar
  237. 237.
    Hunsaker MR, Greco C, Tassone F et al. Rare intranuclear inclusions in the brains of three older adult males with fragile X syndrome: implications for the spectrum of fragile X-associated disorders. JNEN. under review.Google Scholar
  238. 238.
    Chen Y, Tassone F, Berman RF et al. Murine hippocampal neurons expressing Fmr1 gene premutations show early developmental deficits and late degeneration. Hum Mol Genet 2010; 19(1):196–208.PubMedGoogle Scholar
  239. 239.
    Ross-Inta C, Omanska-Klusek A, Wong S et al. Evidence of mitochondrial dysfunction in fragile X-associated tremor/ataxia syndrome. Biochem J 2010; 429(3):545–552.PubMedGoogle Scholar
  240. 240.
    Loesch DZ, Godler DE, Evans A et al. Evidence for the toxicity of bidirectional transcripts and mitochondrial dysfunction in blood associated with small CGG expansions in the FMR1 gene in patients with parkinsonism. Genet Med 2011; Jan 25. [Epub ahead of print].Google Scholar
  241. 241.
    Ladd PD, Smith LE, Rabaia NA et al. An antisense transcript spanning the CGG repeat region of FMR1 is upregulated in premutation carriers but silenced in full mutation individuals. Hum Mol Genet 2007; 16(24):3174–3187.PubMedGoogle Scholar
  242. 242.
    Khalil AM, Faghihi MA, Modarresi F et al. A novel RNA transcript with antiapoptotic function is silenced in fragile X syndrome. PLoS ONE 2008; 3(1):e1486.PubMedGoogle Scholar
  243. 243.
    Welt CK, Smith PC, Taylor AE. Evidence of early ovarian aging in fragile X premutation carriers. J Clin Endocrinol Metab 2004; 89(9):4569–4574.PubMedGoogle Scholar
  244. 244.
    De Caro JJ, Dominguez C, Sherman SL. Reproductive health of adolescent girls who carry the FMR1 premutation: expected phenotype based on current knowledge of fragile x-associated primary ovarian insufficiency. Ann N Y Acad Sci 2008; 1135:99–111.PubMedGoogle Scholar
  245. 245.
    Schwartz CE, Dean J, Howard-Peebles PN et al. Obstetrical and gynecological complications in fragile X carriers: a multicenter study. Am J Med Genet 1994; 51(4):400–402.PubMedGoogle Scholar
  246. 246.
    Allingham-Hawkins DJ, Babul-Hirji R, Chitayat D et al. 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 1999; 83:322–325.PubMedGoogle Scholar
  247. 247.
    Murray A, Ennis S, MacSwiney F et al. Reproductive and menstrual history of females with fragile X expansions. Eur J Hum Genet 2000; 8(4):247–252.PubMedGoogle Scholar
  248. 248.
    Vianna-Morgante AM, Costa SS. Premature ovarian failure is associated with maternally and paternally inherited premutation in Brazilian families with fragile X [see comments] [letter]. American Journal of Human Genetics 2000; 67(1):254–255; discussion 256-258.PubMedGoogle Scholar
  249. 249.
    Sherman SL. Premature ovarian failure in the fragile X syndrome. Am J Med Genet (Semin Med Genet) 2000; 97(3): 189–194.Google Scholar
  250. 250.
    Tejada MI, Garcia-Alegria E, Bilbao A et al. Analysis of the molecular parameters that could predict the risk of manifesting premature ovarian failure in female premutation carriers of fragile X syndrome. Menopause 2008; 15(5):945–949.PubMedGoogle Scholar
  251. 251.
    Ennis S, Ward D, Murray A. Nonlinear association between CGG repeat number and age of menopause in FMR1 premutation carriers. Eur J Hum Genet 2006; 14(2):253–255.PubMedGoogle Scholar
  252. 252.
    Allen EG, Sullivan AK, Marcus M et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 2007:dem 148.Google Scholar
  253. 253.
    Hunter JE, Epstein MP, Tinker SW et al. Fragile X-associated primary ovarian insufficiency: evidence for additional genetic contributions to severity. Genetic Epidemiology 2008; 32(6):553–559.PubMedGoogle Scholar
  254. 254.
    Pankratz VS, de Andrade M, Therneau TM. Random-effects Cox proportional hazards model: general variance components methods for time-to-event data. Genetic Epidemiology 2005; 28(2):97–109.PubMedGoogle Scholar
  255. 255.
    Lin Y-S, Yang M-L. Familial premature ovarian failure in female premutated carriers of fragile X syndrome: a Case Report and Literature Review. Taiwanese Journal of Obstetrics and Gynecology 2006; 45(1):60–63.PubMedGoogle Scholar
  256. 256.
    Miano M, Laperuta C, Chiurazzi P et al. Ovarian dysfunction and FMR1 alleles in a large Italian family with POF and FRAXA disorders: case report. BMC Medical Genetics 2007; 8(1): 18.PubMedGoogle Scholar
  257. 257.
    Hundscheid RDL, Braat DDM, Kiemeney LALM et al. Increased serum FSH in female fragile X premutation carriers with either regular menstrual cycles or on oral contraceptives. Hum Reprod 2001; 16(3):457–462.PubMedGoogle Scholar
  258. 258.
    Murray A, Webb J, MacSwiney F et al. Serum concentrations of follicle stimulating hormone may predict premature ovarian failure in FRAXA premutation women. Hum Reprod 1999; 14(5):1217–1218.PubMedGoogle Scholar
  259. 259.
    Hundscheid RD, Smits AP, Thomas CM et al. Female carriers of fragile X premutations have no increased risk for additional diseases other than premature ovarian failure. American Journal of Medical Genetics 2003; 117(1):6–9.Google Scholar
  260. 260.
    Allen EG, Sullivan AK, Marcus M et al. Examination of reproductive aging milestones among women who carry the FMR1 premutation. Hum Reprod 2007; 22(8):2142–2152.PubMedGoogle Scholar
  261. 261.
    Peprah E, He W, Allen E et al. Examination of FMR1 transcript and protein levels among 74 premutation carriers. J Hum Genet 2010; 55(1):66–68.PubMedGoogle Scholar
  262. 262.
    Burgess B, Partington M, Turner G et al. Normal age of menarche in fragile X syndrome. American Journal of Medical Genetics 1996; 64(2):376–376.PubMedGoogle Scholar
  263. 263.
    Vianna-Morgante AM. Twinning and premature ovarian failure in premutation fragile X carriers. Am J Med Genet 1999; 83(4):326.PubMedGoogle Scholar
  264. 264.
    Van Esch H, Buekenhout L, Race V et al. Very early premature ovarian failure in two sisters compound heterozygous for the FMR1 premutation. Eur J Med Genet 2009; 52(1):37–40.PubMedGoogle Scholar
  265. 265.
    Patsalis PC, Sismani C, Hettinger JA et al. Frequencies of “grey-zone” and premutation-size FMR1 CGG-repeat alleles in patients with developmental disability in Cyprus and Canada. Am J Med Genet 1999; 84(3): 195–197.PubMedGoogle Scholar
  266. 266.
    Loesch DZ, Bui QM, Huggins RM et al. Transcript levels of the intermediate size or grey zone fragile X mental retardation 1 alleles are raised and correlate with the number of CGG repeats. J Med Genet 2007; 44(3): 198–204.Google Scholar
  267. 267.
    Murray A, Youings S, Dennis N et al. Population screening at the FRAXA and FRAXE loci: molecular analyses of boys with learning difficulties and their mothers. Hum Mol Genet 1996; 5(6):727–735.PubMedGoogle Scholar
  268. 268.
    Mazzocco MM, Sonna NL, Teisl JT et al. The FMR1 and FMR2 mutations are not common etiologies of academic difficulty among school-age children. J Dev Behav Pediatr 1997; 18(6):392–398.PubMedGoogle Scholar
  269. 269.
    Mazzocco MMM, Myers GF, Hamner JL et al. The prevalence of the FMR1 and FMR2 mutations among preschool children with language delay. The Journal of Pediatrics 1998; 132(5):795–801.PubMedGoogle Scholar
  270. 270.
    Haddad LA, Aguiar MJ, Costa SS et al. Fully mutated and gray-zone FRAXA alleles in Brazilian mentally retarded boys. Am J Med Genet 1999; 84(3):198–201.PubMedGoogle Scholar
  271. 271.
    Loesch DZ, Godler DE, Khaniani M et al. Linking the FMR1 alleles with small CGG expansions with neurodevelopmental disorders: preliminary data suggest an involvement of epigenetic mechanisms. American Journal of Medical Genetics 2009; 149A(10):2306–2310PubMedGoogle Scholar
  272. 272.
    Bretherick KL, Fluker MR, Robinson WP. FMR1 repeat sizes in the gray zone and high end of the normal range are associated with premature ovarian failure. Hum Genet 2005; 117(4):376–382.PubMedGoogle Scholar
  273. 273.
    Bodega B, Bione S, Dalpra L et al. Influence of intermediate and uninterrupted FMR1 CGG expansions in premature ovarian failure manifestation. Hum Reprod 2006; 21(4):952–957.PubMedGoogle Scholar
  274. 274.
    Streuli I, Fraisse T, Ibecheole V et al. Intermediate and premutation FMR1 alleles in women with occult primary ovarian insufficiency. Fertil Steril 2009; 92(2):464–470.PubMedGoogle Scholar
  275. 275.
    Gleicher N, Weghofer A, Barad DH. A pilot study of premature ovarian senescence: I. Correlation of triple CGG repeats on the FMR1 gene to ovarian reserve parameters FSH and anti-Mullerian hormone. Fertil Steril 2009; 91(5):1700–1706.Google Scholar
  276. 276.
    Chatterjee S, Maitra A, Kadam S et al. CGG repeat sizing in the FMR1 gene in Indian women with premature ovarian failure. Reprod Biomed Online 2009; 19(2):281–286.PubMedGoogle Scholar
  277. 277.
    Schapira A, Hartmann A, Agid Y. Parkinsonian Disorders in Clinical Practice. Oxford, UK: Wiley-Blackwell; 2009.Google Scholar
  278. 278.
    Loesch DZ, Bui QM, Dissanayake C et al. Molecular and cognitive predictors of the continuum of autistic behaviours in fragile X. Neurosci Biobehav Rev 2007; 31(3):315–326.PubMedGoogle Scholar
  279. 279.
    Hagerman RJ, Hall DA, Coffey S et al. Treatment of fragile X-associatedtremor ataxia syndrome (FXTAS) and related neurological problems. Clin Interv Aging 2008; 3(2):251–262.PubMedGoogle Scholar
  280. 280.
    Hagerman RJ, Hagerman PJ. Fragile X Syndrome: Diagnosis, Treatment and Research. 3rd edition. Baltimore: The Johns Hopkins University Press; 2002.Google Scholar
  281. 281.
    Erickson CA, Stigler KA, Posey DJ et al. Aripiprazole in autism spectrum disorders and fragile X syndrome. Neurotherapeutics 2010; 7(3):258–263.PubMedGoogle Scholar
  282. 282.
    Huber KM, Gallagher SM, Warren ST et al. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci USA 2002; 99(11):7746–7750.PubMedGoogle Scholar
  283. 283.
    Bear MF, Huber KM, Warren ST. ThemGluR theory offragile X mental retardation. Trends in Neurosciences 2004; 27(7):370–377.PubMedGoogle Scholar
  284. 284.
    Yan QJ, Ranimai M, Tranfaglia M et al. Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 2005; 49(7): 1053–1066.PubMedGoogle Scholar
  285. 285.
    de Vrij FM, Levenga J, van der Linde HC et al. Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiology of Disease 2008; 31(1):127–132.PubMedGoogle Scholar
  286. 286.
    Berry-Kravis E, Hessl D, Coffey S et al. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. Journal of Medical Genetics 2009; 46(4):266–271.PubMedGoogle Scholar
  287. 287.
    Berry-Kravis E, Cherubini M, Zarevics P et al. Arbaclofen for the Treatment of Children and Adults with Fragile X Syndrome: Results of a Phase 2, Randomized, Double-Blind, Placebo-Controlled, Crossover Study [Abstract]. Paper presented at: International Meeting for Autism Research; 2010; Philadelphia, PA.Google Scholar
  288. 288.
    Bilousova TV, Dansie L, Ngo M et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. Journal of Medical Genetics 2009; 46(2):94–102.PubMedGoogle Scholar
  289. 289.
    Utari A, Chonchaiya W, Rivera SM et al. Side effects of minocycline treatment in patients with fragile x syndrome and exploration of outcome measures. Am J Intellect Dev Disabil 2010; 115(5):433–443.PubMedGoogle Scholar
  290. 290.
    de Diego-Otero Y, Romero-Zerbo Y, el Bekay R et al. Alpha-tocopherol protects against oxidative stress in the fragile X knockout mouse: an experimental therapeutic approach for the Fmrl deficiency. Neuropsychopharmacology 2009; 34(4):1011–1026.PubMedGoogle Scholar
  291. 291.
    Wirojanan J, Jacquemont S, Diaz R 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 2009; 5(2):145–150.PubMedGoogle Scholar
  292. 292.
    Romero-Zerbo Y, Decara J, el Bekay R et al. Protective effects of melatonin against oxidative stress in Fmrl knockout mice: atherapeutic research model forthe fragile X syndrome. J Pineal Res 2009; 46(2):224–234.PubMedGoogle Scholar
  293. 293.
    Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics 2010; 7(3):264–274.PubMedGoogle Scholar

Copyright information

© Landes Bioscience and Springer Science+Business Media 2012

Authors and Affiliations

  1. 1.Department of PsychologyLaTrobe UniversityMelbourneAustralia
  2. 2.Department of Pediatrics, MIND InstituteUniversity of California at Davis Medical CenterSacramentoUSA

Personalised recommendations