Abstract
No studies to date have prospectively examined early autism spectrum disorder (ASD) markers in infants with fragile X syndrome (FXS), who are at elevated risk for ASD. This paper describes the developmental profiles of eight infants with FXS from 9 to 24 months of age. Four meet diagnostic criteria for ASD at 24 months of age, and four do not. Trends in these case studies suggest that early social-communicative deficits differentiate infants with and without later ASD diagnoses in ways that are similar to later-born siblings of children with ASD. Repetitive behaviors and cognitive and adaptive impairments are present in all FXS infants throughout development, suggesting that these deficits reflect the general FXS phenotype and not ASD in FXS specifically.
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References
American Psychiatric Association (2013). Diagnostic and Statistical Manual of Mental Disorders (5th edn.). Washington, DC: American Psychiatric Association.
Bailey, D. B., Hatton, D. D., Skinner, M., & Mesibov, G. (2001). Autistic behavior, FMR1 protein, and developmental trajectories in young males with Fragile X syndrome. Journal of Autism and Developmental Disorders, 31(2), 165–174.
Bailey, D. B., Sideris, J., Roberts, J., & Hatton, D. (2008). Child and genetic variables associated with maternal adaptation to fragile X syndrome: A multidimensional analysis. American Journal of Medical Genetics Part A, 146(6), 720–729.
Bedford, R., Elsabbagh, M., Gliga, T., Pickles, A., Senju, A., Charman, T., et al. (2012). Precursors to social and communication difficulties in infants at-risk for autism: Gaze following and attentional engagement. Journal of Autism and Developmental Disorders, 42(10), 2208–2218. doi:10.1007/s10803-012-1450-y.
Brian, J., Bryson, S. E., Garon, N., Roberts, W., Smith, I. M., Szatmari, P., et al. (2008). Clinical assessment of autism in high-risk 18-month-olds. Autism: The international journal of research and practice, 12(5), 433–456. doi:10.1177/1362361308094500.
Bryson, S. E., Zwaigenbaum, L., Brian, J., Roberts, W., Szatmari, P., Rombough, V., et al. (2006). A prospective case series of high-risk infants who developed autism. Journal of Autism and Developmental Disorders, 37(1), 12–24. doi:10.1007/s10803-006-0328-2.
Bryson, S. E., Zwaigenbaum, L., McDermott, C., Rombough, V., & Brian, J. (2008). The autism observation scale for infants: Scale development and reliability data. Journal of Autism and Developmental Disorders, 38(4), 731–738. doi:10.1007/s10803-007-0440-y.
Budimirovic, D. B., Bukelis, I., Cox, C., Gray, R. M., Tierney, E., & Kaufmann, W. E. (2006). Autism spectrum disorder in fragile X syndrome: Differential contribution of adaptive socialization and social withdrawal. American Journal of Medical Genetics Part A, 140A, 1814–1826.
CDC. (2014). Prevalence of autism spectrum disorder among children aged 8 years: Autism and developmental disabilities monitoring network, 11 sites, United States, 2010. Morbidity and Mortality Weekly Report Surveillance Summaries, 64(SS02), 1–21.
Chawarska, K., Macari, S., & Shic, F. (2013). Decreased spontaneous attention to social scenes in 6-month-old infants later diagnosed with autism spectrum disorders. Biological Psychiatry, 74(3), 195–203. doi:10.1016/j.biopsych.2012.11.022.
Christensen, L., Hutman, T., Rozga, A., Young, G. S., Ozonoff, S., Rogers, S. J., et al. (2010). Play and developmental outcomes in infant siblings of children with autism. Journal of Autism and Developmental Disorders, 40(8), 946–957. doi:10.1007/s10803-010-0941-y.
Clifford, S. M., Hudry, K., Elsabbagh, M., Charman, T., Johnson, M. H., et al. (2013). Temperament in the first 2 years of life in infants at high-risk for autism spectrum disorders. Journal of Autism and Developmental Disorders, 43(3), 673–686. doi:10.1007/s10803-012-1612-y.
Coffee, B., Keith, K., Albizua, I., Malone, T., Mowrey, J., Sherman, S. L., et al. (2009). Incidence of fragile X syndrome by newborn screening for methylated FMR1 DNA. American Journal of Human Genetics, 85(4), 503–514.
Cohen, D., Pichard, N., & Tordjman, S. (2005). Specific genetic disorders and autism: clinical contribution towards their identification. Journal of Autism and Developmental Disorders, 35(1), 103–116.
Damiano, C. R., Nahmias, A., Hogan-Brown, A. L., & Stone, W. L. (2013). What do repetitive and stereotyped movements mean for infant siblings of children with autism spectrum disorders? Journal of Autism and Developmental Disorders, 43(6), 1326–1335. doi:10.1007/s10803-012-1681-y.
Estes, A., Zwaigenbaum, L., Gu, H. B., St John, T., Paterson, S., Elison, J, T., et al. (2015). Behavioral, cognitive, and adaptive development in infants with autism spectrum disorder in the first 2 years of life. Journal of Neurodevelopmental Disorders, 7, 10. doi:10.1186/s11689-015-9117-6.
Fernandez-Carvajal, I., Walichiewicz, P., Xiaosen, X., Pan, R., Hagerman, P. J., & Tassone, F. (2009). Screening for expanded alleles of the FMR1 gene in blood spots from newborn males in a Spanish population. Journal of Molecular Diagnostics, 11(4), 324–329.
Filliter, J. H., Longard, J., Lawrence, M. A., Zwaigenbaum, L., Brian, J., Garon, N., et al. (2015). Positive affect in infant siblings of children diagnosed with autism spectrum disorder. Journal of Abnormal Child Psychology, 43(3), 567–575. doi:10.1007/s10802-014-9921-6.
Gammer, I., Bedford, R., Elsabbagh, M., Garwood, H., Pasco, G., Tucker, L., et al. (2015). Behavioural markers for autism in infancy: Scores on the Autism Observational Scale for Infants in a prospective study of at-risk siblings. Infant Behavior & Development, 38, 107–115. doi:10.1016/j.infbeh.2014.12.017.
Garon, N., Bryson, S. E., Zwaigenbaum, L., Smith, I. M., Brian, J., Roberts, W., et al. (2009). Temperament and its relationship to autistic symptoms in a high-risk infant sib cohort. Journal of Abnormal Child Psychology, 37(1), 59–78. doi:10.1007/s10802-008-9258-0.
Garon, N., Zwaigenbaum, L., Bryson, S., Smith, I. M., Brian, J., Roncadin, C., et al. (2016). Temperament and its association with autism symptoms in a high-risk population. Journal of Abnormal Child Psychology, 44(4), 757–769. doi:10.1007/s10802-015-0064-1.
Gartstein, M. A., & Rothbart, M. K. (2003). Studying infant temperament via the Revised Infant Behavior Questionnaire. Infant Behavior and Development, 26(1), 64–86. doi:10.1016/s0163-6383(02)00169-8.
Gliga, T., Bedford, R., Charman, T., Johnson, M. H., & Team, B. (2015). Enhanced visual search in infancy predicts emerging autism symptoms. Current Biology, 25(13), 1727–1730. doi:10.1016/j.cub.2015.05.011.
Hall, S. S., Lightbody, A. A., Hirt, M., Rezvani, A., & Reiss, A. L. (2010). Autism in fragile X syndrome: A category mistake? Journal of the American Academy of Child and Adolescent Psychiatry, 49(9), 921–933.
Harris, S. W., Hessl, D., Goodlin-Jones, B. L., Ferranti, J., Bacalman, S., Barbato, I., et al. (2008). Autism profiles of males with fragile X syndrome. American Journal on Mental Retardation, 113(6), 427–438. doi:10.1352/2008.113:427-438.
Hunter, J. E., Rivero-Arias, O., Angelov, A., Kim, E., Fotheringham, I., & Leal, J. (2014). Epidemiology of fragile X syndrome: A systematic review and meta-analysis. American Journal of Medical Genetics Part A, 16A, 1648–1658.
Jones, E. J. H., Gliga, T., Bedford, R., Charman, T., & Johnson, M. H. (2014). Developmental pathways to autism: A review of prospective studies of infants at risk. Neuroscience and Biobehavioral Reviews, 39, 1–33. doi:10.1016/j.neubiorev.2013.12.001.
Jones, E. J. H., Venema, K., Earl, R., Lowy, R., Barnes, K., Estes, A., et al. (2016). Reduced engagement with social stimuli in 6-month-old infants with later autism spectrum disorder: A longitudinal prospective study of infants at high familial risk. Journal of Neurodevelopmental Disorders, 8, 7. doi:10.1186/s11689-016-9139-8.
Jones, W., & Klin, A. (2013). Attention to eyes is present but in decline in 2-6-month-old infants later diagnosed with autism. Nature, 504(7480), 427–431. doi:10.1038/nature12715.
Kaufmann, W. E., Cortell, R., Kau, A. S., Bukelis, I., Tierney, E., Gray, R. M., et al. (2004). Autism spectrum disorder in fragile X syndrome: Communication, social interaction, and specific behaviors. American Journal of Medical Genetics Part A, 129A(3), 225–234. doi:10.1002/ajmg.a.30229.
Kidd, S. A., Lachiewicz, A., Barbouth, D., Blitz, R. K., Delahunty, C., McBrien, D., et al. (2014). Fragile X syndrome: A review of associated medical problems. Pediatrics, 134(5), 995–1005. doi:10.1542/peds.2013-4301.
Lord, C., Petkova, E., Hus, V., Gan, W., Lu, F., Martin, D. M., et al. (2012). A multisite study of the clinical diagnosis of different autism spectrum disorders. Archives of General Psychiatry, 69(3), 306–313.
Lord, C., Risi, S., DiLavore, P. C., Shulman, C., Thurm, A., & Pickles, A. (2006). Autism from 2 to 9 years of age. Archives of General Psychiatry, 63, 694–701.
Lord, C., Rutter, M., DiLavore, P. C., Risi, S., Gotham, K., & Bishop, S. L. (2012). Autism Diagnostic Observation Schedule, Second Edition (ADOS-2). Los Angeles, CA: Western Psychological Services.
Mullen, E. M. (1995). Mullen Scales Of Early Learning. Circle Pines, MN: American Guidance Service.
Oakes, A., Thurman, A. J., McDuffie, A., Bullard, L. M., Hagerman, R. J., & Abbeduto, L. (2016). Characterising repetitive behaviours in young boys with fragile X syndrome. Journal of Intellectual Disability Research, 60(1), 54–67.
Ozonoff, S., Young, G. S., Carter, A., Messinger, D., Yirmiya, N., Zwaigenbaum, L., et al. (2011). Recurrence risk for autism spectrum disorders: A Baby Siblings Research Consortium study. Pediatrics, 128(3), e1–e8. doi:10.1542/peds.2010-2825.
Parade, S. H., & Leerkes, E. M. (2008). The reliability and validity of the Infant Behavior Questionnaire-Revised. Infant Behavior & Development, 31(4), 637–646. doi:10.1016/j.infbeh.2008.07.009.
Putnam, S. P., Gartstein, M. A., & Rothbart, M. K. (2006). Measurement of fine-grained aspects of toddler temperament: The early childhood behavior questionnaire. Infant Behavior & Development, 29(3), 386–401. doi:10.1016/j.infbeh.2006.01.004.
Putnam, S. P., Rothbart, M. K., & Gartstein, M. A. (2008). Homotypic and heterotypic continuity of fine-grained temperament during infancy, toddlerhood, and early childhood. Infant and Child Development, 17(4), 387–405. doi:10.1002/icd.582.
Roberts, J. E., Hatton, D. D., Long, A. C., Anello, V., & Colombo, J. (2012). Visual attention and autistic behavior in infants with fragile X syndrome. Journal of Autism and Developmental Disorders, 42(6), 937–946.
Roberts, J. E., McCary, L. M., Shinkareva, S. V., & Bailey, D. B. (2016). Infant development in fragile X syndrome: Cross-syndrome comparisons. Journal of Autism and Developmental Disorders, 46(6), 2088–2099.
Roberts, J. E., Tonnsen, B. L., McCary, L. M., Caravella, K. E., & Shinkareva, S. V. (2016). Brief report: Autism symptoms in infants with fragile X syndrome. Journal of Autism and Developmental Disorders, 46(12), 3830–3837. doi: 10.1007/s10803-016-2903-5.
Roberts, J. E., Tonnsen, B. L., Robinson, A., & Shinkareva, S. V. (2012). Heart activity and autistic behavior in infants and toddlers with fragile X syndrome. American Journal on Intellectual and Developmental Disabilities, 117(2), 90–102. doi:10.1352/1944-7558-117.2.90.
Rogers, S. J., Wehner, D. E., & Hagerman, R. (2001). The behavioral phenotype in fragile X: Symptoms of autism in very young children with fragile X syndrome, idiopathic autism, and other developmental disorders. Journal of Developmental Behavioral Pediatrics, 22(6), 409–417.
Sacrey, L. A. R., Bryson, S. E., & Zwaigenbaum, L. (2013). Prospective examination of visual attention during play in infants at high-risk for autism spectrum disorder: A longitudinal study from 6 to 36 months of age. Behavioural Brain Research, 256, 441–450. doi:10.1016/j.bbr.2013.08.028.
Sparrow S. S., Balla D. A., & Cicchetti D. V. (1984). Vineland Adaptive Behavior Scales. Circle Pines, MN: American Guidance Service.
Sparrow, S. S., Cicchetti, D. V., & Balla, D. A. (2005). Vineland Adaptive Behavior Scales—Second Edition. Circle Pines, MN: American Guidance Service.
Thurman, A. J., McDuffie, A., Kover, S. T., Hagerman, R. J., & Abbeduto, L. (2015). Autism symptomatology in boys with fragile X syndrome: A cross-sectional developmental trajectories comparison with nonsyndromic autism spectrum disorder. Journal of Autism and Developmental Disorders, 45(9), 2816–2832. doi:10.1007/s10803-015-2443-4..
Tonnsen, B. L., Malone, P. S., Hatton, D. D., & Roberts, J. E. (2013). Early negative affect predicts anxiety, not autism, in preschool boys with fragile X syndrome. Journal of Abnormal Child Psychology, 41(2), 267–280. doi:10.1007/s10802-012-9671-2.
Wolff, J. J., Bodfish, J. W., Hazlett, H. C., Lightbody, A. A., Reiss, A. L., & Piven, J. (2012). Evidence of a distinct behavioral phenotype in young boys with fragile X syndrome and autism. Journal of the American Academy of Child & Adolescent Psychiatry, 51(12), 1324–1332.
Yu, T. W., & Berry-Kravis, E. (2014). Autism and fragile X syndrome. Seminars in Neurology, 34(3), 258–265. doi:10.1055/s-0034-1386764.
Zwaigenbaum, L., Bryson, S., & Garon, N. (2013). Early identification of autism spectrum disorders. Behavioural Brain Research, 251, 133–146. doi:10.1016/j.bbr.2013.04.004.
Zwaigenbaum, L., Bryson, S., Rogers, T., Roberts, W., Brian, J., & Szatmari, P. (2005). Behavioral manifestations of autism in the first year of life. International Journal of Developmental Neuroscience, 23(2–3), 143–152.
Acknowledgments
The authors are grateful to the families who participated in this research. Special thanks to John Colombo for his thoughtful feedback on an earlier draft of this manuscript. This research was funded by the National Institute of Mental Health (R01MH107573; R01MH090194; PI: Roberts).
Author Contribution
AH participated in the design and coordination of the study, performed the statistical analyses, and drafted the manuscript; KC compiled data and drafted the case summaries; LR and JE assisted with drafting the manuscript; KH led the clinical diagnostic procedures and contributed to the case summaries. JR conceived of the study and assisted with drafting the manuscript. All authors read and approved the final manuscript.
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Hogan, A.L., Caravella, K.E., Ezell, J. et al. Autism Spectrum Disorder Symptoms in Infants with Fragile X Syndrome: A Prospective Case Series. J Autism Dev Disord 47, 1628–1644 (2017). https://doi.org/10.1007/s10803-017-3081-9
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DOI: https://doi.org/10.1007/s10803-017-3081-9