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Prevalence Studies on Fragile X Alleles in Autism

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Comprehensive Guide to Autism

Abstract

Fragile X syndrome (FXS) is considered the most common form of inherited intellectual disabilities resulting from a single-gene mutation. The real incidence of this syndrome is not known, but epidemiological studies indicate between 1 in 4,000–6,000 males and 1 in 7,000–10,000 females of European descent are affected. The prevalence of autism in individuals with FXS is reported to be approximately 18–36 % in males and 20–23 % in females. From the clinical point of view, the entire spectrum of autism is represented in children with FXS. A large percentage of individuals have some symptoms of autism, such as poor eye contact, unusual hand mannerisms, and reiterative speech, among others, even though they may not meet the full criteria for an autism spectrum disorder (ASD). Furthermore, 90 % of children with FXS display behavioral alterations which resemble ASD, such as social anxiety, gaze avoidance, sensory hypersensitivity, tactile defensiveness, stereotypic movements, poor motor coordination, delayed speech development, and echolalia. On the other hand, 3–6 % of individuals diagnosed with autism present FXS. Regarding premutation carriers, the rates of ASD reported vary among the different studies. From 14 % to 19 % of males and 1 % to 5 % of females may also present ASD. Greater knowledge of the neuropathology and neurobiological abnormalities in FXS is leading to the development of promising targets for treating the symptoms of autism. In this chapter we review the current knowledge on the relationship between the FXS and the ASD and summarize and discuss recent research elucidating the importance of FXS alleles in the ASD.

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References

  • Abrahams BS, Geschwind DH. Advances in autism genetics: on the threshold of a new neurobiology. Nat Rev Genet. 2008;9:341–55.

    Article  PubMed  Google Scholar 

  • American Psychiatric Association. American Psychiatric Association DSM-5 development. 2011. http://www.dsm5.org.

  • Ashley Jr CT, Wilkinson KD, Reines D, Warren ST. FMR1 protein: conserved RNP family domains and selective RNA binding. Science. 1993;262:563–6.

    Article  PubMed  Google Scholar 

  • Bailey Jr DB, 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:2060–9.

    Article  PubMed  Google Scholar 

  • Belmonte MK, Bourgeron T. Fragile X syndrome and autism at the intersection of genetic and neural networks. Nat Neurosci. 2006;9:1221–5.

    Article  PubMed  Google Scholar 

  • Bennetto L, Pennington BF, Porter D, et al. Profile of cognitive functioning in women with the fragile X mutation. Neuropsychology. 2001;15:290–9.

    Article  PubMed  Google Scholar 

  • Budimirovic DB, Kaufmann WE. What can we learn about autism from studying fragile X syndrome? Dev Neurosci. 2011;33:379–94.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Coffey SM, Cook K, Tartaglia N, et al. Expanded clinical phenotype of women with the FMR1 premutation. Am J Med Genet A. 2008;146A:1009–16.

    Article  PubMed  Google Scholar 

  • 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;94:5401–4.

    Article  PubMed  Google Scholar 

  • Crawford DC, Meadows KL, Newman JL, et al. Prevalence and phenotype consequence of FRAXA and FRAXE alleles in a large, ethnically diverse, special education-needs population. Am J Hum Genet. 1999;64:495–507.

    Article  PubMed  Google Scholar 

  • Darnell JC, Van Driesche SJ, Zhang C, et al. FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism. Cell. 2011;146:247–61.

    Article  PubMed  Google Scholar 

  • De Rubeis S, Bagni C. Regulation of molecular pathways in the fragile X syndrome: insights into Autism Spectrum Disorders. J Neurodev Disord. 2011;3:257–69.

    Article  PubMed  Google Scholar 

  • Eichler EE, Holden JJ, Popovich BW, et al. Length of uninterrupted CGG repeats determines instability in the FMR1 gene. Nat Genet. 1994;8:88–94.

    Article  PubMed  Google Scholar 

  • Eichler EE, Hammond HA, Macpherson JN, et al. Population survey of the human FMR1 CGG repeat substructure suggests biased polarity for the loss of AGG interruptions. Hum Mol Genet. 1995;4:2199–208.

    Article  PubMed  Google Scholar 

  • Fernandez-Carvajal I, Walichiewicz P, Xiaosen X, et al. Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. J Mol Diagn. 2009a;11:324–9.

    Article  PubMed  Google Scholar 

  • 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. 2009b;11:306–10.

    Article  PubMed  Google Scholar 

  • Fombonne E. Epidemiology of autistic disorder and other pervasive developmental disorders. J Clin Psychiatry. 2005;66 Suppl 10:3–8.

    PubMed  Google Scholar 

  • Gallagher A, Hallahan B. Fragile X-associated disorders: a clinical overview. J Neurol. 2012;259:401–13.

    Article  PubMed  Google Scholar 

  • Galloway JN, Nelson DL. Evidence for RNA-mediated toxicity in the fragile X-associated tremor/ataxia syndrome. Future Neurol. 2009;4:785.

    Article  PubMed  Google Scholar 

  • Garcia-Arocena D, Hagerman PJ. Advances in understanding the molecular basis of FXTAS. Hum Mol Genet. 2010;19:R83–9.

    Article  PubMed  Google Scholar 

  • García-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:1911–16.

    Article  PubMed  Google Scholar 

  • Greco CM, Hagerman RJ, Tassone F, et al. Neuronal intranuclear inclusions in a new cerebellar tremor/ataxia syndrome among fragile X carriers. Brain. 2002;125:1760–71.

    Article  PubMed  Google Scholar 

  • Haddad LA, Aguiar MJ, Costa SS, Mingroni-Netto RC, Vianna-Morgante AM, Pena SD. Fully mutated and gray-zone FRAXA alleles in Brazilian mentally retarded boys. Am J Med Genet. 1999;84:198–201.

    Article  PubMed  Google Scholar 

  • Hagerman RJ. Physical and behavioral phenotype. In: Hagerman RJ, Hagerman PJ, editors. Fragile X syndrome: diagnosis, treatment and research. 3rd ed. Baltimore: The Johns Hopkins University Press; 2002.

    Google Scholar 

  • Hagerman PJ, Hagerman RJ. The fragile-X premutation: a maturing perspective. Am J Hum Genet. 2004;74:805–16.

    Article  PubMed  Google Scholar 

  • 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.

    Article  PubMed  Google Scholar 

  • Hall SS, Lightbody AA, Hirt M, et al. Autism in fragile X syndrome: a category mistake? J Am Acad Child Adolesc Psychiatry. 2010;49:921–33.

    Article  PubMed  Google Scholar 

  • Harris SW, Hessl D, Goodlin-Jones B, et al. Autism profiles of males with fragile X syndrome. Am J Ment Retard. 2008;113:427–38.

    Article  PubMed  Google Scholar 

  • Hoeffer CA, Sanchez E, Hagerman RJ, et al. Altered signaling and enhanced CYFIP2 expression levels in subjects with fragile X syndrome. Genes Brain Behav. 2012;11:332–41.

    Article  PubMed  Google Scholar 

  • Hunsaker MR, Goodrich-Hunsaker NJ, Willemsen R, et al. Temporal ordering deficits in female CGG KI mice heterozygous for the fragile X premutation. Behav Brain Res. 2010;213:263–8.

    Article  PubMed  Google Scholar 

  • Jacquemont S, Hagerman RJ, Leehey M, et al. Fragile X premutation tremor/ataxia syndrome: molecular, clinical, and neuroimaging correlates. Am J Hum Genet. 2003;72:869–78.

    Article  PubMed  Google Scholar 

  • Johnston C, Eliez S, Dyer-Friedman J, et al. Neurobehavioral phenotype in carriers of the fragile X premutation. Am J Med Genet. 2001;103:314–19.

    Article  PubMed  Google Scholar 

  • 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 A. 2004;129A:225–34.

    Article  PubMed  Google Scholar 

  • Kielinen M, Rantala H, Timonen E, et al. Associated medical disorders and disabilities in children with autistic disorder: a population-based study. Autism. 2004;8:49–60.

    Article  PubMed  Google Scholar 

  • 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:13–23.

    Article  PubMed  Google Scholar 

  • Loesch DZ, Huggins RM, Hagerman RJ. Phenotypic variation and FMRP levels in fragile X. Ment Retard Dev Disabil Res Rev. 2004;10:31–41.

    Article  PubMed  Google Scholar 

  • 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;31:315–26.

    Article  PubMed  Google Scholar 

  • Losh M, Klusek J, Martin GE, et al. Defining genetically meaningful language and personality traits in relatives of individuals with fragile X syndrome and relatives of individuals with autism. Am J Med Genet B Neuropsychiatr Genet. 2012;159B:660–842.

    Article  PubMed  Google Scholar 

  • Lubs HA. A marker X chromosome. Am J Hum Genet. 1969;21:231–44.

    PubMed  Google Scholar 

  • Madrigal I, Xunclà M, Tejada MI, et al. Intermediate FMR1 alleles and cognitive and/or behavioural phenotypes. Eur J Hum Genet. 2011;19:921–3.

    Article  PubMed  Google Scholar 

  • Mandel JL, Biancalana V. Fragile X mental retardation syndrome: from pathogenesis to diagnostic issues. Growth Horm IGF Res. 2004;14:S158–65.

    Article  PubMed  Google Scholar 

  • Martin JB, Bell J. A pedigree of mental defect showing sex-linkage. J Neurol Psychiatry. 1943;6:154–7.

    Article  PubMed  Google Scholar 

  • Mitchell RJ, Holden JJ, Zhang C, et al. FMR1 alleles in Tasmania: a screening study of the special educational needs population. Clin Genet. 2005;67:38–46.

    Article  PubMed  Google Scholar 

  • Mornet E, Chateau C, Simon-Bouy B, et al. The intermediate alleles of the fragile X CGG repeat in patients with mental retardation. Clin Genet. 1998;53:200–1.

    Article  PubMed  Google Scholar 

  • Murray A, Youings S, Dennis N, et al. Population screening at the FRAXA and FRAXE loci: molecular analyses of boys with learning disabilities. Hum Mol Genet. 1996;5:727–35.

    Article  PubMed  Google Scholar 

  • Nowicki ST, Tassone F, Ono MY, et al. The Prader-Willi phenotype of fragile X syndrome. J Dev Behav Pediatr. 2007;28:133–8.

    Article  PubMed  Google Scholar 

  • Oberle I, Rousseau F, Heitz D, et al. Instability of a 550-base pair DNA segment and abnormal methylation in fragile X syndrome. Science. 1991;252:1097–102.

    Article  PubMed  Google Scholar 

  • Otsuka S, Sakamoto Y, Siomi H, et al. Fragile X carrier screening and FMR1 allele distribution in the Japanese population. Brain Dev. 2010;32:110–14.

    Article  PubMed  Google Scholar 

  • Paluszkiewicz SM, Martin BS, Huntsman MM. Fragile X syndrome: the GABAergic system and circuit dysfunction. Dev Neurosci. 2011;33:349–64.

    Article  PubMed  Google Scholar 

  • 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;84:195–7.

    Article  PubMed  Google Scholar 

  • Qin M, Entezam A, Usdin K, et al. A mouse model of the fragile X premutation: effects on behavior, dendrite morphology, and regional rates of cerebral protein synthesis. Neurobiol Dis. 2011;42:85–98.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Rife M, Badenas C, Mallolas J, et al. Incidence of fragile X in 5,000 consecutive newborn males. Genet Test. 2003;7:339–43.

    Article  PubMed  Google Scholar 

  • Rodriguez-Revenga L, Madrigal I, Alegret M, et al. Evidence of depressive symptoms in fragile-X syndrome premutated females. Psychiatr Genet. 2008;18:153–5.

    Article  PubMed  Google Scholar 

  • 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;17:1359–62.

    Article  PubMed  Google Scholar 

  • 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. Am J Hum Genet. 1995;57:1006–18.

    PubMed  Google Scholar 

  • Schaefer GB, Mendelsohn NJ. Genetics evaluation for the etiologic diagnosis of autism spectrum disorders. Genet Med. 2008;10:4–12.

    Article  PubMed  Google Scholar 

  • Sebat J, Lakshmi B, Malhotra D, et al. Strong association of de novo copy number mutations with autism. Science. 2007;316:445–9.

    Article  PubMed  Google Scholar 

  • Shen Y, Dies KA, Holm IA, et al. Clinical genetic testing for patients with autism spectrum disorders. Pediatrics. 2010;125:e727–35.

    Article  PubMed  Google Scholar 

  • Simonoff E, Pickles A, Charman T, et al. Psychiatric disorders in children with autism spectrum disorders: prevalence, comorbidity, and associated factors in a population-derived sample. J Am Acad Child Adolesc Psychiatry. 2008;47:921–9.

    Article  PubMed  Google Scholar 

  • Siomi H, Siomi MC, Nussbaum RL, et al. The protein product of the fragile X gene, FMR1, has characteristics of an RNA-binding protein. Cell. 1993;74:291–8.

    Article  PubMed  Google Scholar 

  • Tamanini F, Willemsen R, van Unen L, et al. Differential expression of FMR1, FXR1 and FXR2 proteins in human brain and testis. Hum Mol Genet. 1997;6:1315–22.

    Article  PubMed  Google Scholar 

  • Tan H, Li H, Jin P. RNA-mediated pathogenesis in fragile X-associated disorders. Neurosci Lett. 2009;466:103–8.

    Article  PubMed  Google Scholar 

  • Tassone F, Hagerman PJ. Expression of the FMR1 gene. Cytogenet Genome Res. 2003;100:124–8.

    Article  PubMed  Google Scholar 

  • Tassone F, Hagerman RJ, Iklé DN, et al. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet. 1999;84:250–61.

    Article  PubMed  Google Scholar 

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

    Article  PubMed  Google Scholar 

  • Tassone F, Hagerman RJ, Taylor AK, et al. Clinical involvement and protein expression in individuals with the FMR1 premutation. Am J Med Genet. 2000b;91:144–52.

    Article  PubMed  Google Scholar 

  • 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;65:905–14.

    Article  PubMed  Google Scholar 

  • Wang LW, Berry-Kravis E, Hagerman RJ. Fragile X: leading the way for targeted treatments in autism. Neurotherapeutics. 2010;7:264–74.

    Article  PubMed  Google Scholar 

  • Willemsen R, Oostra BA, Bassell GJ, et al. The fragile X syndrome: from molecular genetics to neurobiology. Ment Retard Dev Disabil Res Rev. 2004;10:60–7.

    Article  PubMed  Google Scholar 

  • Youings SA, Murray A, Dennis N, et al. FRAXA and FRAXE: the results of a five year survey. J Med Genet. 2000;37:415–21.

    Article  PubMed  Google Scholar 

  • Yu S, Pritchard M, Kremer E, et al. Fragile X genotype characterized by an unstable region of DNA. Science. 1991;252:1179–81.

    Article  PubMed  Google Scholar 

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Acknowledgements

This work was supported by the following sources: FIS PI12/00879 from Instituto de Salud Carlos III and Fondo Europeo de Desarrollo Regional (Fondos FEDER), AGAUR (SGR1337) from Generalitat de Catalunya, and Fundación Alicia Koplowitz (AKOPLOWITZ11_006). The CIBER de Enfermedades Raras is an initiative of the ISCIII

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Authors and Affiliations

  1. Biochemistry and Molecular Genetics Department, Hospital Clínic, C/Villarroel, 170, 08036, Barcelona, Spain

    Laia Rodriguez-Revenga, Irene Madrigal & Montserrat Mila

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  1. Laia Rodriguez-Revenga
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  2. Irene Madrigal
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  3. Montserrat Mila
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Correspondence to Montserrat Mila .

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Editors and Affiliations

  1. Department of Biomedical Sciences, University of Westminster, Faculty of Science & Technology, London, United Kingdom

    Vinood B. Patel

  2. Nutritional Sciences Division and Genomics Centre, King's College London, London, United Kingdom

    Victor R. Preedy

  3. Faculty of Society and Health, Buckinghamshire New University, Middlesex, United Kingdom

    Colin R. Martin

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Rodriguez-Revenga, L., Madrigal, I., Mila, M. (2014). Prevalence Studies on Fragile X Alleles in Autism. In: Patel, V., Preedy, V., Martin, C. (eds) Comprehensive Guide to Autism. Springer, New York, NY. https://doi.org/10.1007/978-1-4614-4788-7_185

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  • DOI: https://doi.org/10.1007/978-1-4614-4788-7_185

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