Summary
Two different mutations in the FMR1 gene may lead to autism. The full mutation, with >200 CGG repeats in the 5′ end of FMR1, leads to hypermethylation and transcriptional silencing of FMR1, resulting in absence or deficiency of the protein product, FMRP. Deficiency of FMRP in the brain causes fragile X syndrome (FXS). Autism occurs in approximately 30% of those with FXS, and pervasive developmental disorders-not otherwise specified occur in an additional 30%. FMRP is an RNA binding protein that modulates receptor-mediated dendritic translation; deficiency leads to dysregulation of many proteins important for synaptic plasticity. Group I metabotropic glutamate receptor (mGluR1/5) activated translation is upregulated in FXS, and new targeted treatments that act on this system include mGluR5 antagonists and GABA agonists, which may reverse the cognitive and behavioral deficits in FXS. Matrix metalloproteinase 9 (MMP-9) is one of the proteins elevated in FXS, and minocycline reduces excess MMP-9 activity in the Fmr1 knockout mouse model of FXS. Both minocycline and mGluR5 antagonists are currently being evaluated in patients with FXS through controlled treatment trials. The premutation (55–200 CGG repeats) may also contribute to the mechanism of autism in approximately 10% of males and 2–3% of females. Premutations with <150 repeats exert cellular effects through a different molecular mechanism, one that involves elevated levels of FMR1 mRNA, CGG-mediated toxicity to neurons, early cell death, and fragile X-associated tremor/ataxia syndrome. In those with large premutations (150–200), lowered levels of FMRP also occur.
Key Words
Fragile X syndrome autism ASD mGluR GABA treatment animal modelReferences
- 1.Hagerman RJ, Rivera SM, Hagerman PJ. The fragile X family of disorders: a model for autism and targeted treatments. Curr Pediatr Rev 2008;4: 40–52.CrossRefGoogle Scholar
- 2.Reddy KS. Cytogenetic abnormalities and fragile-X syndrome in autism spectrum disorder. BMC Med Genet 2005;6: 3.PubMedCrossRefGoogle Scholar
- 3.van Karnebeek CD, Jansweijer MC, Leenders AG, Offringa M, Hennekam RC. Diagnostic investigations in individuals with mental retardation: a systematic literature review of their usefulness. Eur J Hum Genet 2005;13: 6–25.PubMedCrossRefGoogle Scholar
- 4.Femandez-Carvajal I, Walichiewicz P, Xiaosen X, Pan R, Hagerman PJ, Tassone F. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn 2009;11: 324–329.CrossRefGoogle Scholar
- 5.Hagerman PJ. The fragile X prevalence paradox [Erratum in: J Med Genet 2008;45:768]. J Med Genet 2008;45: 498–499.PubMedCrossRefGoogle Scholar
- 6.Dombrowski C, Lévesque S, Morel ML, Rouillard P, Morgan K, Rousseau F. Premutation and intermediate-size FMR1 alleles in 10 572 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: 371–378.PubMedCrossRefGoogle Scholar
- 7.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: 905–914.PubMedCrossRefGoogle Scholar
- 8.Qin M, Kang J, Burlin TV, Jiang C, Smith CB. Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the FMR1 null mouse. J Neurosci 2005;25: 5087–5095.PubMedCrossRefGoogle Scholar
- 9.Bassell GJ, Warren ST. Fragile X syndrome: loss of local mRNA regulation alters synaptic development and function. Neuron 2008;60: 201–214.PubMedCrossRefGoogle Scholar
- 10.Tassone F, Hagerman RJ, Iklé DN, et al. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet 1999;84: 250–261.PubMedCrossRefGoogle Scholar
- 11.Loesch DZ, Huggins RM, Hagerman RJ. Phenotypic variation and FMRP levels in fragile X. Ment Retard Dev Disabil Res Rev 2004;10: 31–41.PubMedCrossRefGoogle Scholar
- 12.Rogers SJ, Wehner DE, Hagerman R. The behavioral 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 2001;22: 409–417.PubMedGoogle Scholar
- 13.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: 225–234.PubMedCrossRefGoogle Scholar
- 14.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: 315–326.PubMedCrossRefGoogle Scholar
- 15.Garcia-Nonell C, Ratera ER, Harris S, et al. Secondary medical diagnosis in fragile X syndrome with and without autism spectrum disorder. Am J Med Genet A 2008;146A: 1911–1916.PubMedCrossRefGoogle Scholar
- 16.de Vries BB, Wiegers AM, Smits AP, et al. Mental status of females with an FMR1 gene full mutation. Am J Hum Genet 1996;58: 1025–1032.PubMedGoogle Scholar
- 17.Bennetto L, Pennington BF. Neuropsychology. In: Hagerman RJ, Hagerman PJ, editors. Fragile X syndrome: diagnosis, treatment, and research. 3rd ed. Baltimore: Johns Hopkins University Press, 2002: 206–248.Google Scholar
- 18.Hagerman RJ. Physical and behavioral phenotype. In: Hagerman RJ, Hagerman PJ, editors. Fragile X syndrome: diagnosis, treatment, and research. 3rd ed. Baltimore: Johns Hopkins University Press, 2002: 3–109.Google Scholar
- 19.Cronister A, Schreiner R, Wittenberger M, Amiri K, Harris K, Hagerman RJ. Heterozygous fragile X female: historical, physical, cognitive, and cytogenetic features. Am J Med Genet 1991;38: 269–274.PubMedCrossRefGoogle Scholar
- 20.Sullivan AK, Marcus M, Epstein MP, et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005;20: 402–412.PubMedCrossRefGoogle Scholar
- 21.Wittenberger MD, Hagerman RJ, Sherman SL, et al. The FMR1 premutation and reproduction. Fertil Steril 2007;87: 456–465.PubMedCrossRefGoogle Scholar
- 22.Tassone F, Hagerman RJ, Taylor AK, Gane LW, Godfrey TE, Hagerman PJ. Elevated levels of FMR1 mRNA in carrier males: a new mechanism of involvement in the fragile-X syndrome. Am J Hum Genet 2000;66: 6–15.PubMedCrossRefGoogle Scholar
- 23.Hagerman RJ. Fragile X Syndrome. In: Cassidy SB, Allanson JE, editors. Management of genetic syndromes. 3rd ed. New York: Wiley & Sons, 2010: 397–411.Google Scholar
- 24.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: 460–469.PubMedCrossRefGoogle Scholar
- 25.Hagerman RJ, Leavitt BR, Farzin F, et al. Fragile-X-associated tremor/ataxia syndrome (FXTAS) in females with the FMR1 premutation. Am J Hum Genet 2004;74: 1051–1056.PubMedCrossRefGoogle Scholar
- 26.Coffey SM, Cook K, Tartaglia N, et al. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A 2008;146A: 1009–1016.PubMedCrossRefGoogle Scholar
- 27.Rodriguez-Revenga L, Madrigal I, Alegret M, Santos M, Milà M. Evidence of depressive symptoms in fragile-X syndrome premutated females. Psychiatr Genet 2008;18: 153–155.PubMedCrossRefGoogle Scholar
- 28.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: 3661–3671.PubMedCrossRefGoogle Scholar
- 29.Garcia-Arocena D, Yang JE, Brouwer JR, et al. Fibroblast phenotype in male carriers of FMR1 premutation alleles. Hum Mol Genet 2010;19: 299–312.PubMedCrossRefGoogle Scholar
- 30.Adams JS, Adams PE, Nguyen D, et al. Volumetric brain changes in females with fragile X-associated tremor/ataxia syndrome (FXTAS). Neurology 2007;69: 851–859.PubMedCrossRefGoogle Scholar
- 31.Greco CM, Berman RF, Martin RM, et al. Neuropathology of fragile X-associated tremor/ataxia syndrome (FXTAS). Brain 2006;129: 243–255.PubMedCrossRefGoogle Scholar
- 32.Greco CM, Soontrapomchai K, Wirojanan J, Gould JE, Hagerman PJ, Hagerman RJ. Testicular and pituitary inclusion formation in fragile X associated tremor/ataxia syndrome. J Urol 2007;177: 1434–1437.PubMedCrossRefGoogle Scholar
- 33.Gokden M, Al-Hinti JT, Harik SI. Peripheral nervous system pathology in fragile X tremor/ataxia syndrome (FXTAS). Neuropathology 2009;29: 280–284.PubMedCrossRefGoogle Scholar
- 34.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: 196–208.PubMedCrossRefGoogle Scholar
- 35.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.PubMedCrossRefGoogle Scholar
- 36.Aziz M, Stathopulu E, Callias M, et al. Clinical features of boys with fragile X premutations and intermediate alleles. Am J Med Genet B Neuropsychiatr Genet 2003;121B: 119–127.PubMedCrossRefGoogle Scholar
- 37.Bailey DB Jr, Raspa M, Olmsted M, Holiday DB. Co-occurring conditions associated with FMR1 gene variations: findings from a national parent survey. Am J Med Genet A 2008;146A: 2060–2069.PubMedCrossRefGoogle Scholar
- 38.Hunter JE, Allen EG, Abramowitz A, et al. 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 2008;83: 692–702.PubMedCrossRefGoogle Scholar
- 39.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: 48–60.PubMedCrossRefGoogle Scholar
- 40.Cornish KM, Kogan CS, Li L, Turk J, Jacquemont S, Hagerman RJ. Lifespan changes in working memory in fragile X premutation males. Brain Cogn 2009;69: 551–558.PubMedCrossRefGoogle Scholar
- 41.Moore CJ, Daly EM, Schmitz N, et al. A neuropsychological investigation of male premutation carriers of fragile X syndrome. Neuropsychologia 2004;42: 1934–1947.PubMedCrossRefGoogle Scholar
- 42.Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord 2007;37: 738–747.PubMedCrossRefGoogle Scholar
- 43.Bourgeois J, Seritan A, Casillas E, et al. Lifetime prevalence of mood and anxiety disorders in fragile X premutation carriers. J Clin Psychiatry (in press).Google Scholar
- 44.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: 130–139.PubMedCrossRefGoogle Scholar
- 45.Bourgeois JA, Coffey SM, Rivera SM, et al. A review of fragile X premutation disorders: expanding the psychiatric perspective. J Clin Psychiatry 2009;70: 852–862.PubMedCrossRefGoogle Scholar
- 46.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: 863–873.PubMedCrossRefGoogle Scholar
- 47.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): 775–785.Google Scholar
- 48.Miller LJ, McIntosh DN, McGrath J, et al. Electrodermal responses to sensory stimuli in individuals with fragile X syndrome: a preliminary report. Am J Med Genet 1999;83: 268–279.PubMedCrossRefGoogle Scholar
- 49.Lord C, Rutter M, Le Couteur A. Autism Diagnostic Interview-Revised: a revised version of a diagnostic interview for caregivers of individuals with possible pervasive developmental disorders. J Autism Dev Disord 1994;24: 659–685.PubMedCrossRefGoogle Scholar
- 50.Lord C, Rutter M, DiLavore PC, Risi S. Autism Diagnostic Observation Schedule. Los Angeles, CA: Western Psychological Services, 1999.Google Scholar
- 51.Harris SW, Hessl D, Goodlin-Jones B, et al. Autism profiles of males with fragile X syndrome. Am J Ment Retard 2008;113: 427–438.PubMedCrossRefGoogle Scholar
- 52.Hagerman RJ, Jackson AW 3rd, Levitas A, Rimland B, Braden M. An analysis of autism in fifty males with the fragile X syndrome. Am J Med Genet A 1986;23: 359–374.CrossRefGoogle Scholar
- 53.Bailey DB Jr, Mesibov GB, Hatton DD, Clark RD, Roberts JE, Mayhew L. Autistic behavior in young boys with fragile X syndrome. J Autism Dev Disord 1998;28: 499–508.PubMedCrossRefGoogle Scholar
- 54.Baumgardner TL, Reiss AL, Freund LS, Abrams MT. Specification of the neurobehavioral phenotype in males with fragile X syndrome. Pediatrics 1995;95: 744–752.PubMedGoogle Scholar
- 55.Kerby DS, Dawson BL. Autistic features, personality, and adaptive behavior in males with the fragile X syndrome and no autism. Am J Ment Retard 1994;98: 455–462.PubMedGoogle Scholar
- 56.Merenstein SA, Sobesky WE, Taylor AK, Riddle JE, Tran HX, Hagerman RJ. Molecular-clinical correlations in males with an expanded FMR1 mutation. Am J Med Genet 1996;64: 388–394.PubMedCrossRefGoogle Scholar
- 57.Hall SS, Lightbody AA, Reiss AL. Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome. Am J Ment Retard 2008;113: 44–53.PubMedCrossRefGoogle Scholar
- 58.Bailey A, Bolton P, Butler L, et al. Prevalence of the fragile X anomaly amongst autistic twins and singletons. J Child Psychol Psychiatry 1993;34: 673–688.PubMedCrossRefGoogle Scholar
- 59.Bailey A, Phillips W, Rutter M. Autism: towards an integration of clinical, genetic, neuropsychological, and neurobiological perspectives. J Child Psychol Psychiatry 1996;37: 89–126.PubMedCrossRefGoogle Scholar
- 60.Dykens EM, Volkmar FR. Medical conditions associated with autism. In: Cohen DJ, Volkmar FR, editors. Handbook of autism and pervasive developmental disorders. 2nd ed. New York: John Wiley & Sons, 1997: 388–410.Google Scholar
- 61.Nowicki ST, Tassone F, Ono MY, et al. The Prader-Willi phenotype of fragile X syndrome. J Dev Behav Pediatr 2007;28: 133–138.PubMedCrossRefGoogle Scholar
- 62.Roberts J, Price J, Barnes E, et al. Receptive vocabulary, expressive vocabulary, and speech production of boys with fragile X syndrome in comparison to boys with Down syndrome. Am J Ment Retard 2007;112: 177–193.PubMedCrossRefGoogle Scholar
- 63.Kau AS, Tierney E, Bukelis I, et al. Social behavior profile in young males with fragile X syndrome: characteristics and specificity. Am J Med Genet 2004;126A: 9–17.PubMedCrossRefGoogle Scholar
- 64.Hatton DD, Sideris J, Skinner M, et al. Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP. Am J Med Genet A 2006;140A: 1804–1813.PubMedCrossRefGoogle Scholar
- 65.Lewis P, Abbeduto L, Murphy M, et al. Cognitive, language and social-cognitive skills of individuals with fragile X syndrome with and without autism. J Intellect Disabil Res 2006;50: 532–545.PubMedCrossRefGoogle Scholar
- 66.Chiu S, Wegelin JA, Blank J, et al. Early acceleration of head circumference in children with fragile X syndrome and autism. J Dev Behav Pediatr 2007;28: 31–35.PubMedCrossRefGoogle Scholar
- 67.Courchesne E, Carper R, Akshoomoff N. Evidence of brain overgrowth in the first year of life in autism. JAMA 2003;290: 337–344.PubMedCrossRefGoogle Scholar
- 68.Butler MG, Dasouki MJ, Zhou XP, et al. Subset of individuals with autism spectrum disorders and extreme macrocephaly associated with germline PTEN tumour suppressor gene mutations. J Med Genet 2005;42: 318–321.PubMedCrossRefGoogle Scholar
- 69.Reiss AL, Freund L, Tseng JE, Joshi PK. Neuroanatomy in fragile X females: the posterior fossa. Am J Hum Genet 1991;49: 279–288.PubMedGoogle Scholar
- 70.Mostofsky SH, Mazzocco MM, Aakalu G, Warsofsky IS, Denckla MB, Reiss AL. Decreased cerebellar posterior vermis size in fragile X syndrome: correlation with neurocognitive performance. Neurology 1998;50: 121–130.PubMedGoogle Scholar
- 71.Murakami JW, Courchesne E, Press GA, Yeung-Courchesne R, Hesselink JR. Reduced cerebellar hemisphere size and its relationship to vermal hypoplasia in autism. Arch Neurol 1989;46: 689–694.PubMedGoogle Scholar
- 72.Ciesielski KT, Harris RJ, Hart BL, Pabst HF. Cerebellar hypoplasia and frontal lobe cognitive deficits in disorders of early childhood. Neuropsychologia 1997;35: 643–655.PubMedCrossRefGoogle Scholar
- 73.Pierce K, Courchesne E. Evidence for a cerebellar role in reduced exploration and stereotyped behavior in autism. Biol Psychiatry 2001;49: 655–664.PubMedCrossRefGoogle Scholar
- 74.Mazzocco MM, Kates WR, Baumgardner TL, Freund LS, Reiss AL. Autistic behaviors among girls with fragile X syndrome. J Autism Dev Disord 1997;27: 415–435.PubMedCrossRefGoogle Scholar
- 75.Van Essen DC, Maunsell HH. Hierarchical organization of the functional streams in the visual cortex. Trends Neurosci 1983;6: 370–375.CrossRefGoogle Scholar
- 76.Sagi D, Julesz B. “Where” and “what” in vision. Science 1985;228: 1217–1219.PubMedCrossRefGoogle Scholar
- 77.Kogan CS, Boutet I, Cornish KM, et al. Differential impact of the FMR1 gene on visual processing in fragile X syndrome. Brain 2004;127: 591–601.PubMedCrossRefGoogle Scholar
- 78.Spencer J, O’Brien J, Riggs K, Braddick O, Atkinson J, Wattam-Bell J. Motion processing in autism: evidence for a dorsal stream deficiency. Neuroreport 2000;11: 2765–2767.PubMedCrossRefGoogle Scholar
- 79.Bertone A, Mottron L, Jelenic P, Faubert J. Motion perception in autism: a “complex” issue. J Cogn Neurosci 2003;15: 218–225.PubMedCrossRefGoogle Scholar
- 80.Blake R, Turner LM, Smoski MJ, Pozdol SL, Stone WL. Visual recognition of biological motion is impaired in children with autism. Psychol Sci 2003;14: 151–157.PubMedCrossRefGoogle Scholar
- 81.Hazlett HC, Poe MD, Lightbody AA, et al. Teasing apart the heterogeneity of autism: same behavior, different brains in toddlers with fragile X syndrome and autism. J Neurodev Disord 2009;1: 81–90.PubMedCrossRefGoogle Scholar
- 82.Hagerman RJ, Miller LJ, McGrath-Clarke J, et al. Influence of stimulants on electrodermal studies in fragile X syndrome. Microsc Res Tech 2002;57: 168–173.PubMedCrossRefGoogle Scholar
- 83.Roberts JE, Boccia ML, Bailey DB Jr, Hatton DD, Skinner M. Cardiovascular indices of physiological arousal in boys with fragile X syndrome. Dev Psychobiol 2001;39: 107–123.PubMedCrossRefGoogle Scholar
- 84.Roberts JE, Boccia ML, Hatton DD, Skinner ML, Sideris J. Temperament and vagal tone in boys with fragile X syndrome. J Dev Behav Pediatr 2006;27: 193–201.PubMedCrossRefGoogle Scholar
- 85.Boccia ML, Roberts JE. Behavior and autonomic nervous system function assessed via heart period measures: the case of hyperarousal in boys with fragile X syndrome. Behav Res Methods, Instrum Comput 2000;32: 5–10.CrossRefGoogle Scholar
- 86.Cohen IL. A theoretical analysis of the role of hyperarousal in the learning and behavior of fragile X males. Ment Retard Dev Disabil Res Rev 1995;1: 286–291.CrossRefGoogle Scholar
- 87.Frankland PW, Wang Y, Rosner B, et al. Sensorimotor gating abnormalities in young males with fragile X syndrome and FMR1-knockout mice. Mol Psychiatry 2004;9: 417–425.PubMedCrossRefGoogle Scholar
- 88.Hessl D, Berry-Kravis E, Cordeiro L, et al. Prepulse inhibition in fragile X syndrome: feasibility, reliability, and implications for treatment. Am J Med Genet B Neuropsychiatr Genet 2009;150B: 545–53.PubMedCrossRefGoogle Scholar
- 89.Perry W, Minassian A, Lopez B, Maron L, Lincoln A. Sensorimotor gating deficits in adults with autism. Biol Psychiatry 2007;61: 482–486.PubMedCrossRefGoogle Scholar
- 90.Postma P, Kumari V, Hines M, Gray JA. The relationship between prepulse detection and prepulse inhibition of the acoustic startle reflex. Psychophysiology 2001;38: 377–382.PubMedCrossRefGoogle Scholar
- 91.Greenough WT, Klintsova AY, Irwin SA, Galvez R, Bates KE, Weiler IJ. Synaptic regulation of protein synthesis and the fragile X protein. Proc Natl Acad Sci U S A 2001;98: 7101–7106.PubMedCrossRefGoogle Scholar
- 92.McBride SM, Choi CH, Wang Y, et al. Pharmacological rescue of synaptic plasticity, courtship behavior, and mushroom body defects in a Drosophila model of fragile X syndrome. Neuron 2005;45: 753–764.PubMedCrossRefGoogle Scholar
- 93.Bakker CE, Oostra BA. Understanding fragile X syndrome: insights from animal models. Cytogenet Genome Res 2003;100: 111–123.PubMedCrossRefGoogle Scholar
- 94.Zhang YQ, Bailey AM, Matthies HJ, et al. Drosophila fragile X-related gene regulates the MAP1B homolog Futsch to control synaptic structure and function. Cell 2001;107: 591–603.PubMedCrossRefGoogle Scholar
- 95.Dockendorff TC, Su HS, McBride SM, et al. Drosophila lacking dfmr1 activity show defects in circadian output and fail to maintain courtship interest. Neuron 2002;34: 973–984.PubMedCrossRefGoogle Scholar
- 96.Morales J, Hiesinger PR, Schroeder AJ, et al. Drosophila fragile X protein, DFXR, regulates neuronal morphology and function in the brain. Neuron 2002;34: 961–972.PubMedCrossRefGoogle Scholar
- 97.Lee A, Li W, Xu K, Bogert BA, Su K, Gao FB. Control of dendritic development by the Drosophila fragile X-related gene involves the small GTPase Rac1. Development 2003;130: 5543–5552.PubMedCrossRefGoogle Scholar
- 98.Dolen G, Osterweil E, Rao BS, et al. Collection of fragile X syndrome in mice. Neuron 2007;56: 955–962.PubMedCrossRefGoogle Scholar
- 99.Bear MF, Dolen G, Osterweil E, Nagarajan N. Fragile X: translation in action. Neuropsychopharmacology 2008;33: 84–87.PubMedCrossRefGoogle Scholar
- 100.Penagarikano O, Mulle JG, Warren ST. The pathophysiology of fragile X syndrome. Annu Rev Genomics Hum Genet 2007;8: 109–129.PubMedCrossRefGoogle Scholar
- 101.Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci 2004;27: 370–377.PubMedCrossRefGoogle Scholar
- 102.Bear MF. Therapeutic implications of the mGluR theory of fragile X mental retardation. Genes Brain Behav 2005;4: 393–398.PubMedCrossRefGoogle Scholar
- 103.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: 5401–5404.PubMedCrossRefGoogle Scholar
- 104.Nimchinsky EA, Oberlander AM, Svoboda K. Abnormal development of dendritic spines in FMR1 knock-out mice. J Neurosci 2001;21: 5139–5146.PubMedGoogle Scholar
- 105.Irwin SA, Patel B, Idupulapati M, et al. Abnormal dendritic spine characteristics in the temporal and visual cortices of patients with fragile-X syndrome: a quantitative examination. Am J Med Genet A 2001;98: 161–167.CrossRefGoogle Scholar
- 106.Knott GW, Holtmaat A, Wilbrecht L, Welker E, Svoboda K. Spine growth precedes synapse formation in the adult neocortex in vivo. Nat Neurosci 2006;9: 1117–1124.PubMedCrossRefGoogle Scholar
- 107.Linden DJ. Input-specific induction of cerebellar long-term depression does not require presynaptic alteration. Learn Mem 1994;1: 121–128.PubMedGoogle Scholar
- 108.Anwyl R. Metabotropic glutamate receptors: electrophysiological properties and role in plasticity. Brain Res Brain Res Rev 1999;29: 83–120.PubMedCrossRefGoogle Scholar
- 109.Huber KM, Gallagher SM, Warren ST, Bear MF. Altered synaptic plasticity in a mouse model of fragile X mental retardation. Proc Natl Acad Sci U S A 2002;99: 7746–7750.PubMedCrossRefGoogle Scholar
- 110.Zheng F, Gallagher JP. Metabotropic glutamate receptors are required for the induction of long-term potentiation. Neuron 1992;9: 163–172.PubMedCrossRefGoogle Scholar
- 111.Fendt M, Schmid S. Metabotropic glutamate receptors are involved in amygdaloid plasticity. Eur J Neurosci 2002;15: 1535–1541.PubMedCrossRefGoogle Scholar
- 112.Koekkoek SK, Yamaguchi K, Milojkovic BA, et al. Deletion of FMR1 in Purkinje]ells enhances parallel fiber LTD, enlarges spines, and attenuates cerebellar eyelid conditioning in fragile X syndrome. Neuron 2005;47: 339–352.PubMedCrossRefGoogle Scholar
- 113.Nakamoto M, Nalavadi V, Epstein MP, Narayanan U, Bassell GJ, Warren ST. Fragile X mental retardation protein deficiency leads to excessive mGluR5-dependent internalization of AMPA receptors. Proc Natl Acad Sci U S A 2007;104: 15537–15542.PubMedCrossRefGoogle Scholar
- 114.Irwin SA, Galvez R, Weiler IJ, Beckel-Mitchener A, Greenough WT. Brain structure and functions of FMR1 protein. In: Hagerman RJ, Hagerman PJ, editors. Fragile X syndrome: diagnosis, treatment, and research. 3rd ed. Baltimore: Johns Hopkins University Press, 2002: 191–205.Google Scholar
- 115.Beckel-Mitchener A, Greenough WT. Correlates across the structural, functional, and molecular phenotypes of fragile X syndrome. Ment Retard Dev Disabil Res Rev 2004;10: 53–59.PubMedCrossRefGoogle Scholar
- 116.Chuang SC, Zhao W, Bauchwitz R, Yan Q, Bianchi R, Wong RK. Prolonged epileptiform discharges induced by altered group I metabotropic glutamate receptor-mediated synaptic responses in hippocampal slices of a fragile X mouse model. J Neurosci 2005;25: 8048–8055.PubMedCrossRefGoogle Scholar
- 117.Gasparini F, Lingenhohl K, Stoehr N, et al. 2-Methyl-6-(phenyl-ethynyl)-pyridine (MPEP), a potent, selective and systemically active mGlu5 receptor antagonist. Neuropharmacology 1999;38: 1493–1503.PubMedCrossRefGoogle Scholar
- 118.Yan QJ, Rammal M, Tranfaglia M, Bauchwitz RP. Suppression of two major fragile X syndrome mouse model phenotypes by the mGluR5 antagonist MPEP. Neuropharmacology 2005;49: 1053–1066.PubMedCrossRefGoogle Scholar
- 119.de Vrij FM, Levenga J, van der Linde HC, et al. Rescue of behavioral phenotype and neuronal protrusion morphology in Fmr1 KO mice. Neurobiol Dis 2008;31: 127–132.PubMedCrossRefGoogle Scholar
- 120.Paredes RG, Agmo A. GABA and behavior: the role of receptor subtypes [Erratum in: Neurosci Biobehav Rev 1992;16:425]. Neurosci Biobehav Rev 1992;16: 145–170.PubMedCrossRefGoogle Scholar
- 121.Mihalek RM, Banerjee PK, Korpi ER, et al. Attenuated sensitivity to neuroactive steroids in γ-aminobutyrate type A receptor delta subunit knockout mice. Proc Natl Acad Sci U S A 1999;96: 12905–12910.PubMedCrossRefGoogle Scholar
- 122.Carter RB, Wood PL, Wieland S, et al. Characterization of the anticonvulsant properties of ganaxolone (CCD 1042; 3α-hydroxy-3β-methyl-5α-pregnan-20-one), a selective, high-affinity, steroid modulator of the γ-aminobutyric acidA receptor. J Pharmacol Exp Ther 1997;280: 1284–1295.PubMedGoogle Scholar
- 123.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: 417–431.PubMedCrossRefGoogle Scholar
- 124.D’Hulst C, De Geest N, Reeve SP, et al. Decreased expression of the GABAA receptor in fragile X syndrome. Brain Res 2006;1121: 238–245.PubMedCrossRefGoogle Scholar
- 125.Gantois I, Vandesompele J, Speleman F, et al. Expression profiling suggests underexpression of the GABAA receptor subunit delta in the fragile X knockout mouse model. Neurobiol Dis 2006;21: 346–357.PubMedCrossRefGoogle Scholar
- 126.Chang S, Bray SM, Li Z, et al. Identification of small molecules rescuing fragile X syndrome phenotypes in Drosophila. Nat Chem Biol 2008;4: 256–263.PubMedCrossRefGoogle Scholar
- 127.Isaacson JS, Hille B. GABAB-mediated presynaptic inhibition of excitatory transmission and synaptic vesicle dynamics in cultured hippocampal neurons. Neuron 1997;18: 143–152.PubMedCrossRefGoogle Scholar
- 128.Sohn JW, Lee D, Cho H, et al. Receptor-specific inhibition of GABAB-activated K+ currents by muscarinic and metabotropic glutamate receptors in immature rat hippocampus. J Physiol 2007;580: 411–422.PubMedCrossRefGoogle Scholar
- 129.Primrose DA. Treatment of self-injurious behaviour with a GABA (γ-aminobutyric acid) analogue. J Ment Defic Res 1979;23: 163–173.PubMedGoogle Scholar
- 130.Paylor R. Pharmacological modification of behavioral responses in the fragile X mouse model. Proc Int Fragile X Conf 11th 2008;11: 1052 (abstract). Available at http://www.fragilex.org/ html/2008_proceedings.htm.Google Scholar
- 131.Pacey LK, Heximer SP, Hampson DR. Increased GABAB receptor-mediated signaling reduces the susceptibility of fragile X knockout mice to audiogenic seizures. Mol Pharmacol 2009;76: 18–24.PubMedCrossRefGoogle Scholar
- 132.Porter RH, Jaeschke G, Spooren W, et al. Fenobam: a clinically validated nonbenzodiazepine anxiolytic is a potent, selective, and noncompetitive mGlu5 receptor antagonist with inverse agonist activity. J Pharmacol Exp Ther 2005;315: 711–721.PubMedCrossRefGoogle Scholar
- 133.Beny-Kravis E, Hessl D, Coffey S, et al. A pilot open label, single dose trial of fenobam in adults with fragile X syndrome. J Med Genet 2009;46: 266–271.CrossRefGoogle Scholar
- 134.Hagerman RJ, Beny-Kravis E, Kaufmann WE, et al. Advances in the treatment of fragile X syndrome. Pediatrics 2009;123: 378–390.PubMedCrossRefGoogle Scholar
- 135.Beny-Kravis E, Sumis A, Hervey C, et al. Open-label treatment trial of lithium to target the underlying defect in fragile X syndrome. J Dev Behav Pediatr 2008;29: 293–302.CrossRefGoogle Scholar
- 136.Li J, Pelletier MR, Perez Velazquez JL, Carlen PL. Reduced cortical synaptic plasticity and GluR1 expression associated with fragile X mental retardation protein deficiency. Mol Cell Neurosci 2002;19: 138–151.PubMedCrossRefGoogle Scholar
- 137.Lauterborn JC, Rex CS, Kramár E, et al. Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome. J Neurosci 2007;27: 10685–10694.PubMedCrossRefGoogle Scholar
- 138.Berry-Kravis E, Krause SE, Block SS, et al. Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J Child Adolesc Psychopharmacol 2006;16: 525–540.PubMedCrossRefGoogle Scholar
- 139.Bilousova TV, Rusakov DA, Ethell DW, Ethell IM. Matrix metalloproteinase-7 disrupts dendritic spines in hippocampal neurons through NMDA receptor activation. J Neurochem 2006;97: 44–56.PubMedCrossRefGoogle Scholar
- 140.Bilousova TV, Dansie L, Ngo M, et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet 2009;46: 94–102.PubMedCrossRefGoogle Scholar
- 141.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 (in press).Google Scholar
- 142.McCracken JT, McGough J, Shah B, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med 2002;347: 314–321.PubMedCrossRefGoogle Scholar
- 143.Aman MG, Gharabawi GM; Special Topic Advisory Panel on Transitioning to Risperidone Therapy in Patients With Mental Retardation and Developmental Disabilities. Treatment of behavior disorders in mental retardation: report on transitioning to atypical antipsychotics, with an emphasis on risperidone. J Clin Psychiatry 2004;65: 1197–1210.PubMedCrossRefGoogle Scholar
- 144.Owen R, Sikich L, Marcus RN, et al. Aripiprazole in the treatment of irritability in children and adolescents with autistic disorder. Pediatrics 2009;124: 1533–1540.PubMedCrossRefGoogle Scholar
- 145.Erickson CA, Kohn AE, Diener JT, Stigler KA, Posey DJ, McDougle CJ. A prospective, 12-week open-label study of aripiprazole in fragile X syndrome. Proc Int Fragile X Conf 11th 2008;11: 1065–1100. Available at http://www.fragilex.org/ html/2008_proceedings.htm.Google Scholar