Young children with fragile X syndrome (FXS) often experience anxiety, irritability, and hyperactivity related to sensory hyperarousal. However, there are no medication recommendations with documented efficacy for children under 5 years old of age with FXS. We examined data through a chart review for 45 children with FXS, 12–50 months old, using the Mullen Scales of Early Learning (MSEL) for baseline and longitudinal assessments. All children had clinical level of anxiety, language delays based on MSEL scores, and similar early learning composite (ELC) scores at their first visit to our clinic. Incidence of autism spectrum disorder (ASD) was similar in both groups. There were 11 children who were treated with sertraline, and these patients were retrospectively compared to 34 children who were not treated with sertraline by chart review. The baseline assessments were done at ages ranging from 18 to 44 months (mean 26.9, SD 7.99) and from 12 to 50 months (mean 29.94, SD 8.64) for treated and not treated groups, respectively. Mean rate of improvement in both expressive and receptive language development was significantly higher in the group who was treated with sertraline ( and , resp.). This data supports the need for a controlled trial of sertraline treatment in young children with FXS. 1. Introduction Fragile X syndrome (FXS) is a single gene disorder caused by mutation in the fragile X mental retardation 1 (FMR1) gene located at Xq27.3. The full mutation of CGG repeat expansion (>200 repeats) in the 5′ untranslated region (UTR) region leads to transcriptional silencing of the gene and a lack of fragile X mental retardation protein (FMRP) resulting in FXS [1]. FXS is the most common inherited form of intellectual impairment known, and it is characterized by a broad spectrum of cognitive, behavioral, and emotional impairment. The level of cognitive impairment ranges from borderline to severe intellectual disability (ID), and it correlates with the level of FMRP in blood [2, 3]. The full mutation allele frequency of FXS is about 1 in 4,000 in the general population [4, 5]. FMRP, an RNA binding, stabilizing, and transporter protein, is essential for synaptogenesis and the maturation and pruning processes of dendrite spines during development and throughout life [6–8]. FMRP is also a regulator of translation, typically through suppression, so the lack of FMRP leads to excessive synthesis of proteins [9] and synaptic dysfunction throughout the brain [10]. FMRP is functionally linked to perhaps hundreds of mRNAs [11], so that its absence disrupts the
References
[1]
A. J. M. H. Verkerk, M. Pieretti, J. S. Sutcliffe 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, vol. 65, no. 5, pp. 905–914, 1991.
[2]
W. E. Kaufmann, M. T. Abrams, W. Chen, and A. L. Reiss, “Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome,” American Journal of Medical Genetics, vol. 83, no. 4, pp. 286–295, 1999.
[3]
D. Z. Loesch, R. M. Huggins, and R. J. Hagerman, “Phenotypic Variation and FMRP Levels in Fragile X,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 10, no. 1, pp. 31–41, 2004.
[4]
P. J. Hagerman, “The fragile X prevalence paradox,” Journal of Medical Genetics, vol. 45, no. 8, pp. 498–499, 2008.
[5]
F. J. Song, P. Barton, V. Sleightholme, G. L. Yao, and A. Fry-Smith, “Screening for fragile X syndrome: a literature review and modelling study,” Health technology Assessment, vol. 7, no. 16, pp. 1–106, 2003.
[6]
S. A. Irwin, R. Galvez, and W. T. Greenough, “Dendritic spine structural anomalies in fragile-X mental retardation syndrome,” Cerebral Cortex, vol. 10, no. 10, pp. 1038–1044, 2000.
[7]
G. J. Bassell and S. T. Warren, “Fragile X Syndrome: loss of local mRNA regulation alters synaptic development and function,” Neuron, vol. 60, no. 2, pp. 201–214, 2008.
[8]
S. De Rubeis and C. Bagni, “Fragile X mental retardation protein control of neuronal mRNA metabolism: insights into mRNA stability,” Molecular and Cellular Neuroscience, vol. 43, no. 1, pp. 43–50, 2010.
[9]
M. Qin, J. Kang, T. V. Burlin, C. Jiang, and C. B. Smith, “Postadolescent changes in regional cerebral protein synthesis: an in vivo study in the Fmr1 null mouse,” Journal of Neuroscience, vol. 25, no. 20, pp. 5087–5095, 2005.
[10]
F. Zalfa, M. Giorgi, B. Primerano et al., “The Fragile X syndrome protein FMRP associates with BC1 RNA and regulates the translation of specific mRNAs at synapses,” Cell, vol. 112, no. 3, pp. 317–327, 2003.
[11]
J. C. Darnell, S. J. Van Driesche, C. Zhang et al., “FMRP stalls ribosomal translocation on mRNAs linked to synaptic function and autism,” Cell, vol. 146, no. 2, pp. 247–261, 2011.
[12]
R. A. McKinney, “Physiological roles of spine motility: development, plasticity and disorders,” Biochemical Society Transactions, vol. 33, no. 6, pp. 1299–1302, 2005.
[13]
R. J. Hagerman, K. Amiri, and A. Cronister, “Fragile X checklist,” American Journal of Medical Genetics, vol. 38, no. 2-3, pp. 283–287, 1991.
[14]
F. J. Symons, R. D. Clark, D. D. Hatton, M. Skinner, and D. B. Bailey, “Self-injurious behavior in young boys with fragile X syndrome,” American Journal of Medical Genetics, vol. 118, no. 2, pp. 115–121, 2003.
[15]
W. E. Kaufmann, R. Cortell, A. S. M. Kau et al., “Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors,” American Journal of Medical Genetics, vol. 129, no. 3, pp. 225–234, 2004.
[16]
D. B. Budimirovic, I. Bukelis, C. Cox, R. M. Gray, E. Tierney, and W. E. Kaufmann, “Autism spectrum disorder in fragile X syndrome: differential contribution of adaptive socialization and social withdrawal,” American Journal of Medical Genetics A, vol. 140, no. 17, pp. 1814–1826, 2006.
[17]
L. Cordeiro, E. Ballinger, R. Hagerman, and D. Hessl, “Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization,” Journal of Neurodevelopmental Disorders, vol. 3, no. 1, pp. 57–67, 2011.
[18]
S. S. Hall, A. A. Lightbody, and A. L. Reiss, “Compulsive, self-injurious, and autistic behavior in children and adolescents with fragile X syndrome,” American Journal on Mental Retardation, vol. 113, no. 1, pp. 44–72, 2008.
[19]
L. Abbeduto, N. Brady, and S. T. Kover, “Language development and fragile X syndrome: profiles, syndrome- specificity, and within-syndrome differences,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 13, no. 1, pp. 36–46, 2007.
[20]
J. E. Roberts, P. Mirrett, and M. Burchinal, “Receptive and expressive communication development of young males with fragile X syndrome,” American Journal Of Mental Retardation, vol. 106, no. 3, pp. 216–230, 2001.
[21]
A. Philofsky, S. L. Hepburn, A. Hayes, R. Hagerman, and S. J. Rogers, “Linguistic and cognitive functioning and autism symptoms in young children with fragile X syndrome,” American Journal of Mental Retardation, vol. 109, no. 3, pp. 208–218, 2004.
[22]
P. Lewis, L. Abbeduto, M. Murphy et al., “Cognitive, language and social-cognitive skills of individuals with fragile X syndrome with and without autism,” Journal of Intellectual Disability Research, vol. 50, no. 7, pp. 532–545, 2006.
[23]
A. McDuffie, L. Abbeduto, P. Lewis et al., “Autism spectrum disorder in children and adolescents with fragile X syndrome: within-syndrome differences and age-related changes,” American Journal on Intellectual and Developmental Disabilities, vol. 115, no. 4, pp. 307–326, 2010.
[24]
T. E. Davis, B. N. Moree, T. Dempsey et al., “The relationship between autism spectrum disorders and anxiety: the moderating effect of communication,” Research in Autism Spectrum Disorders, vol. 5, no. 1, pp. 324–329, 2011.
[25]
S. W. Harris, D. Hessl, B. Goodlin-Jones et al., “Autism profiles of males with fragile X syndrome,” American Journal on Mental Retardation, vol. 113, no. 6, pp. 427–438, 2008.
[26]
S. T. Kover and L. Abbeduto, “Expressive language in male adolescents with fragile X syndrome with and without comorbid autism,” Journal of Intellectual Disability Research, vol. 54, no. 3, pp. 246–265, 2010.
[27]
D. B. Bailey, D. D. Hatton, G. Mesibov, N. Ament, and M. Skinner, “Early development, temperament, and functional impairment in autism and fragile X syndrome,” Journal of Autism and Developmental Disorders, vol. 30, no. 1, pp. 49–59, 2000.
[28]
C. Zingerevich, L. Greiss-Hess, K. Lemons-Chitwood et al., “Motor abilities of children diagnosed with fragile X syndrome with and without autism,” Journal of Intellectual Disability Research, vol. 53, no. 1, pp. 11–18, 2009.
[29]
D. D. Hatton, J. Sideris, M. Skinner et al., “Autistic behavior in children with fragile X syndrome: prevalence, stability, and the impact of FMRP,” American Journal of Medical Genetics A, vol. 140, no. 17, pp. 1804–1813, 2006.
[30]
G. R. DeLong, C. R. Ritch, and S. Burch, “Fluoxetine response in children with autistic spectrum disorders: correlation with familial major affective disorder and intellectual achievement,” Developmental Medicine and Child Neurology, vol. 44, no. 10, pp. 652–659, 2002.
[31]
R. J. Steingard, B. Zimnitzky, D. R. DeMaso, M. L. Bauman, and J. P. Bucci, “Sertraline treatment of transition-associated anxiety and agitation in children with autistic disorder,” Journal of Child and Adolescent Psychopharmacology, vol. 7, no. 1, pp. 9–15, 1997.
[32]
B. H. King, E. Hollander, L. Sikich et al., “Lack of efficacy of citalopram in children with autism spectrum disorders and high levels of repetitive behavior: citalopram ineffective in children with autism,” Archives of General Psychiatry, vol. 66, no. 6, pp. 583–590, 2009.
[33]
S. Alwan, J. Reefhuis, S. A. Rasmussen, R. S. Olney, and J. M. Friedman, “Use of selective serotonin-reuptake inhibitors in pregnancy and the risk of birth defects,” New England Journal of Medicine, vol. 356, no. 26, pp. 2684–2692, 2007.
[34]
J. H. Krystal, D. F. Tolin, G. Sanacora et al., “Neuroplasticity as a target for the pharmacotherapy of anxiety disorders, mood disorders, and schizophrenia,” Drug Discovery Today, vol. 14, no. 13-14, pp. 690–697, 2009.
[35]
T. C. Bethea and L. Sikich, “Early pharmacological treatment of autism: a rationale for developmental treatment,” Biological Psychiatry, vol. 61, no. 4, pp. 521–537, 2007.
[36]
D. C. Chugani, “Role of altered brain serotonin mechanisms in autism,” Molecular Psychiatry, vol. 7, no. 2, pp. S16–S17, 2002.
[37]
S. R. Chandana, M. E. Behen, C. Juhász et al., “Significance of abnormalities in developmental trajectory and asymmetry of cortical serotonin synthesis in autism,” International Journal of Developmental Neuroscience, vol. 23, no. 2-3, pp. 171–182, 2005.
[38]
J. E. Malberg, A. J. Eisch, E. J. Nestler, and R. S. Duman, “Chronic antidepressant treatment increases neurogenesis in adult rat hippocampus,” Journal of Neuroscience, vol. 20, no. 24, pp. 9104–9110, 2000.
[39]
J. E. Malberg, “Implications of adult hippocampal neurogenesis in antidepressant action,” Journal of Psychiatry and Neuroscience, vol. 29, no. 3, pp. 196–205, 2004.
[40]
J. L. Warner-Schmidt and R. S. Duman, “Hippocampal neurogenesis: opposing effects of stress and antidepressant treatment,” Hippocampus, vol. 16, no. 3, pp. 239–249, 2006.
[41]
X. W. Su, X. Y. Li, M. Banasr et al., “Chronic treatment with AMPA receptor potentiator Org 26576 increases neuronal cell proliferation and survival in adult rodent hippocampus,” Psychopharmacology, vol. 206, no. 2, pp. 215–222, 2009.
[42]
P. Bianchi, E. Ciani, S. Guidi et al., “Early pharmacotherapy restores neurogenesis and cognitive performance in the Ts65Dn mouse model for down syndrome,” Journal of Neuroscience, vol. 30, no. 26, pp. 8769–8779, 2010.
[43]
J. C. Lauterborn, C. S. Rex, E. Kramár et al., “Brain-derived neurotrophic factor rescues synaptic plasticity in a mouse model of fragile X syndrome,” Journal of Neuroscience, vol. 27, no. 40, pp. 10685–10694, 2007.
[44]
R. J. Hagerman, J. C. Lauterborn, and E. Berry-Kravis, “Fragile X Syndrome and targeted treatment trials,” in Modeling the Fragile X Syndrome, R. B. Denman, Ed., Springer, Heidelberg, Germany, 2011.
[45]
C. Lord, S. Risi, L. Lambrecht, et al., Autism Diagnostic Observation Schedule-Generic, W.P. Services, Los Angeles, Calif, USA, 2002.
[46]
A. Le Couteur, M. Rutter, C. Lord et al., “Autism diagnostic interview: a standardized investigator-based instrument,” Journal of Autism and Developmental Disorders, vol. 19, no. 3, pp. 363–387, 1989.
[47]
American Psychiatric Association, Diagnostic and Statistical Manual of Mental Disorders (DSM-IV), American Psychiatric Association, Washington, DC, USA, 4th edition, 1994.
[48]
R. J. Hagerman, E. Berry-Kravis, W. E. Kaufmann et al., “Advances in the treatment of fragile x Syndrome,” Pediatrics, vol. 123, no. 1, pp. 378–390, 2009.
[49]
E. M. Mullen, Mullen Scales of Early Learning (AGS ed.), American Guidance Service, Circle Pines, Minn, USA, 1995.
[50]
D. B. Bailey, et al., “Research on fragile X syndrome and autism: implications for the study of genes, environments, and developmental language disorders,” in Developmental Language Disorders: From Phenotypes to Etiologies, M. L. Rice and S. F. Warren, Eds., Lawrence Erlbaum Associates, Mahwah, NJ, USA, 2004.
[51]
J. E. Roberts, J. B. Mankowski, J. Sideris et al., “Trajectories and predictors of the development of very young boys with fragile X syndrome,” Journal of Pediatric Psychology, vol. 34, no. 8, pp. 827–836, 2009.
[52]
S. Hetrick, S. Merry, J. McKenzie, P. Sindahl, and M. Proctor, “Selective serotonin reuptake inhibitors (SSRIs) for depressive disorders in children and adolescents,” Cochrane Database of Systematic Reviews, no. 3, article CD004851, 2007.
[53]
K. D. Wagner, “Pharmacotherapy for major depression in children and adolescents,” Progress in Neuro-Psychopharmacology and Biological Psychiatry, vol. 29, no. 5, pp. 819–826, 2005.
[54]
G. T. Baranek, J. E. Roberts, F. J. David et al., “Developmental trajectories and correlates of sensory processing in young boys with fragile X syndrome,” Physical and Occupational Therapy in Pediatrics, vol. 28, no. 1, pp. 79–98, 2008.
[55]
P. L. Davies and R. Tucker, “Evidence review to investigate the support for subtypes of children with difficulty processing and integrating sensory information,” American Journal of Occupational Therapy, vol. 64, no. 3, pp. 391–402, 2010.
[56]
K. Cornish, V. Sudhalter, and J. Turk, “Attention and language in Fragile X,” Mental Retardation and Developmental Disabilities Research Reviews, vol. 10, no. 1, pp. 11–16, 2004.
[57]
S. J. Rogers, S. Hepburn, and E. Wehner, “Parent reports of sensory symptoms in toddlers with autism and those with other developmental disorders,” Journal of Autism and Developmental Disorders, vol. 33, no. 6, pp. 631–642, 2003.
[58]
R. M. Meredith, C. D. Holmgren, M. Weidum, N. Burnashev, and H. D. Mansvelder, “Increased threshold for spike-timing-dependent plasticity is caused by unreliable calcium signaling in mice lacking Fragile X gene Fmr1,” Neuron, vol. 54, no. 4, pp. 627–638, 2007.
[59]
L. Restivo, F. Ferrari, E. Passino et al., “Enriched environment promotes behavioral and morphological recovery in a mouse model for the fragile X syndrome,” Proceedings of the National Academy of Sciences of the United States of America, vol. 102, no. 32, pp. 11557–11562, 2005.
[60]
J. Brown, C. M. Cooper-Kuhn, G. Kempermann et al., “Enriched environment and physical activity stimulate hippocampal but not olfactory bulb neurogenesis,” European Journal of Neuroscience, vol. 17, no. 10, pp. 2042–2046, 2003.
[61]
L. W. Wang, E. Berry-Kravis, and R. J. Hagerman, “Fragile X: leading the way for targeted treatments in autism,” Neurotherapeutics, vol. 7, no. 3, pp. 264–274, 2010.
