Fragile X Syndrome

https://doi.org/10.25100/cm.v45i4.1810

Article Sidebar

PDF(EN) PDF(ES) HTML(En) HTML(Es)

Published: Dec 30, 2014
Issue: Vol. 45 No. 4 (2014)
Section Reviews

Publcation metrics

2658 | 975 | 539 | 1828 | 3591




 


Main Article Content

Authors
  • Wilmar Saldarriaga +
  • Flora Tassone +
  • Laura Yuriko González-Teshima +
  • Jose Vicente Forero-Forero +
  • Sebastián Ayala-Zapata +
  • Randi Hagerman +
Abstract
Fragile X Syndrome (FXS) is a genetic disease due to a CGG trinucleotide expansion, named full mutation (greater than 200 CGG repeats), in the fragile X mental retardation 1 gene locus Xq27.3; which leads to an hypermethylated region in the gene promoter therefore silencing it and lowering the expression levels of the fragile X mental retardation 1, a protein involved in synaptic plasticity and maturation.  Individuals with FXS present with intellectual disability, autism, hyperactivity, long face, large or prominent ears and macroorchidism at puberty and thereafter. Most of the young children with FXS will present with language delay, sensory hyper arousal and anxiety. Girls are less affected than boys, only 25% have intellectual disability. Given the genomic features of the syndrome, there are patients with a number of triplet repeats between 55 and 200, known as premutation carriers. Most carriers have a normal IQ but some have developmental problems. The diagnosis of FXS has evolved from karyotype with special culture medium, to molecular techniques that are more sensitive and specific including PCR and Southern Blot. During the last decade, the advances in the knowledge of FXS, has led to the development of investigations on pharmaceutical management or targeted treatments for FXS. Minocycline and sertraline have shown efficacy in children.

Author Biographies

Wilmar Saldarriaga, Professor Morphology, Gynecology and Obstetrics. Hospital Universitario del Valle, Universidad del Valle, Cali, Colombia

Professor Morphology, Gynecology and Obstetrics. Hospital Universitario del Valle, Universidad del Valle, Cali, Colombia

Flora Tassone, Department of Biochemistry and Molecular Medicine; UC Davis MIND Institute, University of California, Sacramento, USA

Research Biochemist, Department of Biochemistry and Molecular Medicine; UC Davis MIND Institute, University of California, Sacramento, USA.

Laura Yuriko González-Teshima, Medicine and surgery School, University of Valle. Cali, Colombia

Medicine and surgery School, University of Valle. Cali, Colombia

Jose Vicente Forero-Forero, Medicine and surgery School, University of Valle. Cali, Colombia

Medicine and surgery School, University of Valle. Cali, Colombia

Sebastián Ayala-Zapata, Medicine and surgery School, University of Valle. Cali, Colombia

Medicine and surgery School, University of Valle. Cali, Colombia

Randi Hagerman, Medical director and distinguished professor. Holder Research Chair in Fragile X syndrome. Department of Pediatrics, School of Medicine. UC Davis MIND Institute, University of California, Davis, USA.

Medical director and distinguished professor. Holder Research Chair in Fragile X syndrome. Department of Pediatrics, School of Medicine. UC Davis MIND Institute, University of California, Davis, USA.

How to Cite
Saldarriaga, W., Tassone, F., González-Teshima, L. Y., Forero-Forero, J. V., Ayala-Zapata, S., & Hagerman, R. (2014). Fragile X Syndrome. Colombia Medica, 45(4), 190–198. https://doi.org/10.25100/cm.v45i4.1810
References

Martin JP, Bell J. A PEDIGREE OF MENTAL DEFECT SHOWING SEX-LINKAGE. J Neurol Psychiatry [Internet]. 1943 Jul [cited 2014 Aug 31];6(3-4):154–7. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1090429&tool=pmcentrez&rendertype=abstract

Hagerman RJ, Hagerman PJ. Fragile X Syndrome: Diagnosis, Treatment, and Research. 3rd ed. Hagerman RJ, Hagerman PJ, editors. Baltimore: The John Hopkins University Press; 2002.

Enfermedades C para el C de. Fragile X síndrome (FXS). [Internet]. Prevención, Centro para el Control de Enfermedades y. 2013. Available from: http://www.cdc.gov/ncbddd/fxs/index.html

Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest [Internet]. 2012 Dec 3 [cited 2014 Aug 24];122(12):4314–22. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3533539&tool=pmcentrez&rendertype=abstract

Liu Y, Winarni T, Zhang L, Tassone F, Hagerman R. Fragile X-associated tremor/ataxia syndrome (FXTAS) in grey zone carriers. Clin Genet. 2013;84:74–7.

Hall D, Tassone F, Klepitskaya O, Leehey M. Fragile X Associated Tremor ataxia syndrome in FMR1 gray zone allele carriers. Movement Disorders. 2012. p. 297–301.

Bagni C, Tassone F, Neri G, Hagerman R. Fragile X syndrome: causes, diagnosis, mechanisms, and therapeutics. J Clin Invest. 2012 Dec;122(12):4314–22.

Coffee B, Keith K, Albizua I, Malone T, Mowrey J, Sherman SL, et al. Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. Am J Hum Genet [Internet]. 2009 Oct [cited 2014 Aug 28];85(4):503–14. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2756550&tool=pmcentrez&rendertype=abstract

Hirst MC, Knight SJ, Christodoulou Z, Grewal PK, Fryns JP, Davies KE. Origins of the fragile X syndrome mutation. J Med Genet [Internet]. 1993 Aug [cited 2014 Aug 31];30(8):647–50. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=1016491&tool=pmcentrez&rendertype=abstract

Gardeazábal Alvarez G. El divino. Bogotá: Plaza & Janés; 1986.

Fernandez-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 [Internet]. 2009 Jul [cited 2014 Mar 25];11(4):324–9. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2710709&tool=pmcentrez&rendertype=abstract

Pietrobono R, Tabolacci E, Zalfa F, Zito I, Terracciano A, Moscato U, et al. Molecular dissection of the events leading to inactivation of the FMR1 gene. Hum Mol Genet [Internet]. 2005 Jan 15 [cited 2014 Aug 31];14(2):267–77. Available from: http://hmg.oxfordjournals.org/content/14/2/267.long

Pieretti M, Zhang FP, Fu YH, Warren ST, Oostra BA, Caskey CT, et al. Absence of expression of the FMR-1 gene in fragile X syndrome. Cell [Internet]. 1991 Aug 23 [cited 2014 Aug 31];66(4):817–22. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1878973

Naumann A, Hochstein N, Weber S, Fanning E, Doerfler W. A distinct DNA-methylation boundary in the 5’- upstream sequence of the FMR1 promoter binds nuclear proteins and is lost in fragile X syndrome. Am J Hum Genet [Internet]. 2009 Dec [cited 2014 Aug 31];85(5):606–16. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2775827&tool=pmcentrez&rendertype=abstract

Stöger R, Kajimura TM, Brown WT, Laird CD. Epigenetic variation illustrated by DNA methylation patterns of the fragile-X gene FMR1. Hum Mol Genet [Internet]. 1997 Oct [cited 2014 Aug 31];6(11):1791–801. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9302255

Malter HE, Iber JC, Willemsen R, de Graaff E, Tarleton JC, Leisti J, et al. Characterization of the full fragile X syndrome mutation in fetal gametes. Nat Genet [Internet]. 1997 Mar [cited 2014 Aug 31];15(2):165–9. Available from: http://www.ncbi.nlm.nih.gov/pubmed/9020841

Sutcliffe JS, Nelson DL, Zhang F, Pieretti M, Caskey CT, Saxe D, et al. DNA methylation represses FMR-1 transcription in fragile X syndrome. Hum Mol Genet [Internet]. 1992 Oct [cited 2014 Aug 31];1(6):397–400. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1301913

OMIM Entry - # 300624 - FRAGILE X MENTAL RETARDATION SYNDROME [Internet]. [cited 2014 Aug 31]. Available from: http://www.omim.org/entry/300624

Siomi H, Siomi MC, Nussbaum RL, Dreyfuss G. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell [Internet]. 1993 Jul 30 [cited 2014 Aug 31];74(2):291–8. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7688265

Ashley CT, Wilkinson KD, Reines D, Warren ST. FMR1 protein: conserved RNP family domains and selective RNA binding. Science [Internet]. 1993 Oct 22 [cited 2014 Aug 26];262(5133):563–6. Available from: http://www.ncbi.nlm.nih.gov/pubmed/7692601

Darnell JC, Van Driesche SJ, Zhang C, Hung KYS, Mele A, Fraser CE, et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell [Internet]. 2011 Jul 22 [cited 2014 Jul 23];146(2):247–61. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3232425&tool=pmcentrez&rendertype=abstract

Brown V, Jin P, Ceman S, Darnell JC, O’Donnell WT, Tenenbaum SA, et al. Microarray identification of FMRP-associated brain mRNAs and altered mRNA translational profiles in fragile X syndrome. Cell [Internet]. 2001 Dec 16 [cited 2014 Aug 31];107(4):477–87. Available from: http://www.ncbi.nlm.nih.gov/pubmed/11719188

Chen L, Yun SW, Seto J, Liu W, Toth M. The fragile X mental retardation protein binds and regulates a novel class of mRNAs containing U rich target sequences. Neuroscience [Internet]. 2003 Jan [cited 2014 Aug 31];120(4):1005–17. Available from: http://www.ncbi.nlm.nih.gov/pubmed/12927206

Bear MF, Huber KM, Warren ST. The mGluR theory of fragile X mental retardation. Trends Neurosci [Internet]. 2004 Jul [cited 2014 Jul 10];27(7):370–7. Available from: http://www.ncbi.nlm.nih.gov/pubmed/15219735

Gatto CL, Broadie K. Genetic controls balancing excitatory and inhibitory synaptogenesis in neurodevelopmental disorder models. Front Synaptic Neurosci [Internet]. 2010 Jan [cited 2014 Aug 22];2:4. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3059704&tool=pmcentrez&rendertype=abstract

Verkerk AJ, Pieretti M, Sutcliffe JS, Fu YH, Kuhl DP, Pizzuti A, 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 [Internet]. 1991 May 31 [cited 2014 Aug 28];65(5):905–14. Available from: http://www.ncbi.nlm.nih.gov/pubmed/1710175

Nolin SL, Brown WT, Glicksman A, Houck GE, Gargano AD, Sullivan A, et al. Expansion of the fragile X CGG repeat in females with premutation or intermediate alleles. Am J Hum Genet [Internet]. 2003 Mar [cited 2014 Aug 31];72(2):454–64. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=379237&tool=pmcentrez&rendertype=abstract

Fernandez-Carvajal I, Lopez Posadas B, Pan R, Raske C, Hagerman PJ, Tassone F. Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J Mol Diagn [Internet]. 2009 Jul [cited 2014 Aug 31];11(4):306–10. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=2710706&tool=pmcentrez&rendertype=abstract

Fernandez-Carvajal I, Lopez Posadas B, Pan R, Raske C, Hagerman PJ, Tassone F. Expansion of an FMR1 grey-zone allele to a full mutation in two generations. J Mol Diagn. 2009 Jul;11(4):306–10.

Hagerman R, Hagerman P. Advances in clinical and molecular understanding of the FMR1 premutation and fragile X-associated tremor/ataxia syndrome. Lancet Neurol [Internet]. 2013 Aug [cited 2014 Aug 21];12(8):786–98. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3922535&tool=pmcentrez&rendertype=abstract

Berry-Kravis E, Abrams L, Coffey SM, Hall DA, Greco C, Gane LW, et al. Fragile X-associated tremor/ataxia syndrome: clinical features, genetics, and testing guidelines. Mov Disord [Internet]. 2007 Oct 31 [cited 2014 Aug 31];22(14):2018–30, quiz 2140. Available from: http://www.ncbi.nlm.nih.gov/pubmed/17618523

Seltzer MM, Baker MW, Hong J, Maenner M, Greenberg J, Mandel D. Prevalence of CGG expansions of the FMR1 gene in a US population-based sample. Am J Med Genet B Neuropsychiatr Genet [Internet]. 2012 Jul [cited 2014 Mar 20];159B(5):589–97. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3391968&tool=pmcentrez&rendertype=abstract

Bourgeois JA, Cogswell JB, Hessl D, Zhang L, Ono MY, Tassone F, et al. Cognitive, anxiety and mood disorders in the fragile X-associated tremor/ataxia syndrome. Gen Hosp Psychiatry [Internet]. [cited 2014 Aug 31];29(4):349–56. Available from: http://www.pubmedcentral.nih.gov/articlerender.fcgi?artid=3991490&tool=pmcentrez&rendertype=abstract

Martin JR, Arici A. Fragile X and reproduction. Curr Opin Obstet Gynecol. 2008 Jun;20(3):216–20.

Fernandez-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 Jul;11(4):324–9.

Firth H V, Hurst JA, Hall JG. Oxford Desk Reference : Clinical Genetics. Oxford University Press; 2005.

Rueda J-R, Ballesteros J, Guillen V, Tejada M-I, Solà I. Folic acid for fragile X syndrome. Cochrane database Syst Rev [Internet]. 2011;CD008476. Available from: http://www.ncbi.nlm.nih.gov/pubmed/21563169

Detich N, Bovenzi V, Szyf M. Valproate induces replication-independent active DNA demethylation. J Biol Chem. 2003 Jul;278(30):27586–92.

Tabolacci E, De Pascalis I, Accadia M, Terracciano A, Moscato U, Chiurazzi P, et al. Modest reactivation of the mutant FMR1 gene by valproic acid is accompanied by histone modifications but not DNA demethylation. Pharmacogenet Genomics. 2008 Aug;18(8):738–41.

Torrioli M, Vernacotola S, Setini C, Bevilacqua F, Martinelli D, Snape M, et al. Treatment with valproic acid ameliorates ADHD symptoms in fragile X syndrome boys. Am J Med Genet A. 2010 Jun;152A(6):1420–7.

Su T, Fan H-X, Jiang T, Sun W-W, Den W-Y, Gao M-M, et al. Early continuous inhibition of group 1 mGlu signaling partially rescues dendritic spine abnormalities in the Fmr1 knockout mouse model for fragile X syndrome. Psychopharmacology (Berl). 2011 May;215(2):291–300.

Garner SE, Eady EA, Popescu C, Newton J, Li WA. Minocycline for acne vulgaris: efficacy and safety. Cochrane database Syst Rev. 2003 Jan;(1):CD002086.

Bilousova T V, Dansie L, Ngo M, Aye J, Charles JR, Ethell DW, et al. Minocycline promotes dendritic spine maturation and improves behavioural performance in the fragile X mouse model. J Med Genet. 2009 Feb;46(2):94–102.

Mazzieri R, Masiero L, Zanetta L, Monea S, Onisto M, Garbisa S, et al. Control of type IV collagenase activity by components of the urokinase-plasmin system: a regulatory mechanism with cell-bound reactants. EMBO J. 1997 May;16(9):2319–32.

Bruno MA, Cuello AC. Activity-dependent release of precursor nerve growth factor, conversion to mature nerve growth factor, and its degradation by a protease cascade. Proc Natl Acad Sci U S A. 2006 Apr;103(17):6735–40.

Dziembowska M, Milek J, Janusz A, Rejmak E, Romanowska E, Gorkiewicz T, et al. Activity-dependent local translation of matrix metalloproteinase-9. J Neurosci. 2012 Oct;32(42):14538–47.

Wang X, Bozdagi O, Nikitczuk JS, Zhai ZW, Zhou Q, Huntley GW. Extracellular proteolysis by matrix metalloproteinase-9 drives dendritic spine enlargement and long-term potentiation coordinately. Proc Natl Acad Sci U S A. 2008 Dec;105(49):19520–5.

Dziembowska M, Pretto DI, Janusz A, Kaczmarek L, Leigh MJ, Gabriel N, et al. High MMP-9 activity levels in fragile X syndrome are lowered by minocycline. Am J Med Genet A. 2013 Aug;161A(8):1897–903.

Wilczynski GM, Konopacki FA, Wilczek E, Lasiecka Z, Gorlewicz A, Michaluk P, et al. Important role of matrix metalloproteinase 9 in epileptogenesis. J Cell Biol. 2008 Mar;180(5):1021–35.

Indah Winarni T, Chonchaiya W, Adams E, Au J, Mu Y, Rivera SM, et al. Sertraline May Improve Language Developmental Trajectory in Young Children with Fragile X Syndrome: A Retrospective Chart Review. Autism Research and Treatment. 2012. p. 1–8.

Moskowitz LJ, Carr EG, Durand VM. Behavioral intervention for problem behavior in children with fragile X syndrome. Am J Intellect Dev Disabil. 2011 Nov;116(6):457–78.

Turk J. Fragile X syndrome: lifespan developmental implications for those without as well as with intellectual disability. Curr Opin Psychiatry. 2011 Sep;24(5):387–97.

Dew-Hughes D. Educating Children with Fragile X Syndrome: A Multi-Professional View. Routledge, editor. 2003.

Dyer-Friedman J, Glaser B, Hessl D, Johnston C, Huffman LC, Taylor A, et al. Genetic and environmental influences on the cognitive outcomes of children with fragile X syndrome. J Am Acad Child Adolesc Psychiatry. 2002 Mar;41(3):237–44.

Hessl D, Dyer-Friedman J, Glaser B, Wisbeck J, Barajas RG, Taylor A, et al. The influence of environmental and genetic factors on behavior problems and autistic symptoms in boys and girls with fragile X syndrome. Pediatrics. 2001 Nov;108(5):E88.

Usage statistics

Downloads

Download data is not yet available.
Most read articles by the same author(s)
Received 2014-11-20
Accepted 2014-12-17
Published 2014-12-30

The copy rights of the articles published in Colombia Médica belong to the Universidad del Valle. The contents of the articles that appear in the Journal are exclusively the responsibility of the authors and do not necessarily reflect the opinions of the Editorial Committee of the Journal. It is allowed to reproduce the material published in Colombia Médica without prior authorization for non-commercial use