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Journal of Neurodevelopmental Disorders

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Open Access 01-12-2018 | Research

Genetic and maternal predictors of cognitive and behavioral trajectories in females with fragile X syndrome

Authors: Laura del Hoyo Soriano, Angela John Thurman, Danielle Jenine Harvey, W. Ted Brown, Leonard Abbeduto

Published in: Journal of Neurodevelopmental Disorders | Issue 1/2018

Abstract

Background

Fragile X syndrome (FXS) is caused by a mutation in the FMR1 gene on the X chromosome, leading to decreased levels of FMR1 protein (FMRP), which causes the array of neuropsychological impairments that define FXS. Because FXS is an X-linked condition, fewer females display FXS and females with FXS are more mildly affected than males, on average. However, there is a considerable variability in terms of severity of affectedness among females with FXS. The current study was designed to investigate potential genetic (FMRP level and ratio of affected to total chromosomes) and environmental factors (maternal psychological distress and closeness in the mother–child relationship) influencing the cognitive (fluid and crystallized intelligence) and behavioral (anxiety and withdrawal) phenotype of females with FXS.

Methods

We conducted a prospective 3-year longitudinal study of 16 females with FXS (with up to four assessments, each separated by a year) using an accelerated longitudinal design so that we had coverage of the age range of 10–15 years at study start and 13–18 at study end. We focused on both the level of functioning related to chronological age expectations (standard scores) and absolute change in skill (raw scores) over the 3-year period.

Results

At a cross-sectional level, fluid intelligence and crystallized intelligence were both predicted by a closer mother–child relationship and lower maternal psychological distress. However, only fluid intelligence was predicted by a lower ratio of affected to total chromosomes. Anxiety and withdrawal were predicted by a higher ratio of affected to total chromosomes. Withdrawal was also predicted by lower closeness in the mother–child relationship and higher maternal distress. In terms of longitudinal change, gains were observed in fluid and crystallized intelligence, whereas anxious and withdrawn behaviors remained stable over visits. Gains in fluid intelligence were solely predicted by FXS biomarkers (higher FMRP level and lower ratio of affected to total chromosomes), while gains in crystallized intelligence were not predicted by any of the biological and environmental variables.

Conclusions

Our results show that FXS biomarkers and maternal variables contribute differentially to the cognitive and behavioral features of the adolescent female with FXS. These findings can help in the design of treatment studies aimed at enhancing cognitive and behavioral abilities in the FXS population.

Sherman S. Epidemiology. In: Hagerman RJ, Hagerman PJ, editors. Fragile X syndrome: diagnosis, treatment, and research. Johns Hopkins University Press; 2002. p. 136–68.

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. 2009;85(4):503–14. http://www.ncbi.nlm.nih.gov/pubmed/19804849 CrossRefPubMedPubMedCentral

Tassone F. Newborn screening for fragile X syndrome. JAMA Neurol. 2014;71(3):355–9. http://www.ncbi.nlm.nih.gov/pubmed/24395328 CrossRefPubMedPubMedCentral

Gothelf D, Furfaro JA, Hoeft F, Eckert MA, Hall SS, O’Hara R, et al. Neuroanatomy of fragile X syndrome is associated with aberrant behavior and the fragile X mental retardation protein (FMRP). Ann Neurol. 2008;63(1):40–51. http://www.ncbi.nlm.nih.gov/pubmed/17932962 CrossRefPubMedPubMedCentral

Loesch DZ, Huggins RM, Hagerman RJ. Phenotypic variation and FMRP levels in fragile X. Ment Retard Dev Disabil Res Rev. 2004;10(1):31–41. http://www.ncbi.nlm.nih.gov/pubmed/14994286 CrossRefPubMed

Huddleston LB, Visootsak J, Sherman SL. Cognitive aspects of fragile X syndrome. Wiley Interdiscip Rev Cogn Sci. 2014;5(4):501–8. http://www.ncbi.nlm.nih.gov/pubmed/25485036 CrossRefPubMedPubMedCentral

Schwarte AR. Fragile X syndrome. Sch Psychol Q. 2008;23(2):290–300. http://dx.doi.org/10.1037/1045-3830.23.2.290.

Freund LS, Reiss AL. Cognitive profiles associated with the fra(X) syndrome in males and females. Am J Med Genet. 1991;38(4):542–7. http://www.ncbi.nlm.nih.gov/pubmed/2063895 CrossRefPubMed

Reiss AL, Hall SS. Fragile X syndrome: assessment and treatment implications. Child Adolesc Psychiatr Clin N Am. 2007;16(3):663–75. http://www.sciencedirect.com/science/article/pii/S1056499307000296?via%3Dihub CrossRefPubMed

10.

Kogan CS, Boutet I, Cornish K, Graham GE, Berry-Kravis E, Drouin A, et al. A comparative neuropsychological test battery differentiates cognitive signatures of fragile X and Down syndrome. J Intellect Disabil Res. 2009;53(2):125–42. http://doi.wiley.com/10.1111/j.1365-2788.2008.01135.x CrossRefPubMed

11.

Backes M, Gen B, Schreck J, Doerfler W, Lehmkuhl G, von Gontard A. Cognitive and behavioral profile of fragile X boys: correlations to molecular data. Am J Med Genet. 2000;95(2):150–6. http://doi.wiley.com/10.1002/1096-8628%2820001113%2995%3A2%3C150%3A%3AAID-AJMG11%3E3.0.CO%3B2-1 CrossRefPubMed

12.

Kaufmann WE, Abrams MT, Chen W, Reiss AL. Genotype, molecular phenotype, and cognitive phenotype: correlations in fragile X syndrome. Am J Med Genet. 1999;83(4):286–95. http://www.ncbi.nlm.nih.gov/pubmed/10208163 CrossRefPubMed

13.

Bennetto L, Taylor AK, Pennington BF, Porter D, Hagerman RJ. Profile of cognitive functioning in women with the fragile X mutation. Neuropsychology. 2001;15(2):290–9. http://doi.apa.org/getdoi.cfm?doi=10.1037/0894-4105.15.2.290 CrossRefPubMed

14.

Carroll JB. Human cognitive abilities: a survey of factor-analytic studies. New York: Cambridge University Press; 1993.CrossRef

15.

Horn JL, Cattell RB. Refinement and test of the theory of fluid and crystallized general intelligences. J Educ Psychol. 1966;57(5):253–70.CrossRefPubMed

16.

Geake JG, Hansen PC. Functional neural correlates of fluid and crystallized analogizing. NeuroImage. 2010;49(4):3489–97. http://www.ncbi.nlm.nih.gov/pubmed/19761849 CrossRefPubMed

17.

Chen X, Hertzog C, Park DC. Cognitive predictors of everyday problem solving across the lifespan. Gerontology. 2017;63(4):372–84. http://www.ncbi.nlm.nih.gov/pubmed/28273664 CrossRefPubMedPubMedCentral

18.

Niu M, Han Y, Dy ABC, Du J, Jin H, Qin J, et al. Autism symptoms in fragile X syndrome. J Child Neurol. 2017;32(10):903–9. http://www.ncbi.nlm.nih.gov/pubmed/28617074 CrossRefPubMed

19.

Hagerman RJ, Berry-Kravis E, Hazlett HC, Bailey DB, Moine H, Kooy RF, et al. Fragile X syndrome. Nat Rev Dis Prim. 2017;3:17065. http://www.nature.com/articles/nrdp201765 CrossRefPubMed

20.

Gossett A, Sansone S, Schneider A, Johnston C, Hagerman R, Tassone F, et al. Psychiatric disorders among women with the fragile X premutation without children affected by fragile X syndrome. Am J Med Genet B Neuropsychiatr Genet. 2016;171(8):1139–47. https://onlinelibrary.wiley.com/doi/abs/10.1002/ajmg.b.32496.

21.

Angkustsiri K, Wirojanan J, Deprey LJ, Gane LW, Hagerman RJ. Fragile X syndrome with anxiety disorder and exceptional verbal intelligence. Am J Med Genet Part A. 2008;146A(3):376–9. http://doi.wiley.com/10.1002/ajmg.a.32118 CrossRefPubMed

22.

Hatton DD, Wheeler A, Sideris J, Sullivan K, Reichardt A, Roberts J, et al. Developmental trajectories of young girls with fragile X syndrome. Am J Intellect Dev Disabil. 2009;114(3):161–71. http://aaiddjournals.org/doi/pdf/10.1352/1944-7558-114.3.161 CrossRefPubMed

23.

Abbeduto L, Seltzer MM, Shattuck P, Krauss MW, Orsmond G, Murphy MM. Psychological well-being and coping in mothers of youths with autism, Down syndrome, or fragile X syndrome. Am J Ment Retard. 2004;109(3):237. http://www.ncbi.nlm.nih.gov/pubmed/15072518 CrossRefPubMed

24.

Klaiman C, Quintin E-M, Jo B, Lightbody AA, Hazlett HC, Piven J, et al. Longitudinal profiles of adaptive behavior in fragile X syndrome. Pediatrics. 2014;134(2):315–24. http://www.ncbi.nlm.nih.gov/pubmed/25070318 CrossRefPubMedPubMedCentral

25.

Tassone F, Hagerman RJ, Iklé DN, Dyer PN, Lampe M, Willemsen R, et al. FMRP expression as a potential prognostic indicator in fragile X syndrome. Am J Med Genet. 1999;84(3):250–61. http://www.ncbi.nlm.nih.gov/pubmed/10331602 CrossRefPubMed

26.

Ligsay A, Hagerman RJ. Review of targeted treatments in fragile X syndrome. Intractable Rare Dis Res. 2016;5(3):158–67. http://www.ncbi.nlm.nih.gov/pubmed/27672538 CrossRefPubMedPubMedCentral

27.

Kover ST, Pierpont EI, Kim J-S, Brown WT, Abbeduto L. A neurodevelopmental perspective on the acquisition of nonverbal cognitive skills in adolescents with fragile X syndrome. Dev Neuropsychol. 2013;38(7):445–60. http://www.ncbi.nlm.nih.gov/pubmed/24138215 CrossRefPubMed

28.

Hessl D, Dyer-Friedman J, Glaser B, Wisbeck J, Gabriela Barajas R, 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;108(5):e88. http://pediatrics.aappublications.org/content/pediatrics/108/5/e88.full.pdf CrossRefPubMed

29.

Sterling A, Abbeduto L. Language development in school-age girls with fragile X syndrome. J Intellect Disabil Res. 2012;56(10):974–83. http://www.ncbi.nlm.nih.gov/pubmed/22676254 CrossRefPubMedPubMedCentral

30.

Turkstra LS, Abbeduto L, Meulenbroek P. Social cognition in adolescent girls with fragile X syndrome. Am J Intellect Dev Disabil. 2014;119(4):319–39. http://www.ncbi.nlm.nih.gov/pubmed/25007297 CrossRefPubMedPubMedCentral

31.

Hagerman RJ, Jackson C, Amiri K, Silverman a C, O’Connor R, Sobesky W. Girls with fragile X syndrome: physical and neurocognitive status and outcome. Pediatrics. 1992;89(3):395–400.PubMed

32.

Warren SF, Brady N, Sterling A, Fleming K, Marquis J. Maternal responsivity predicts language development in young children with fragile X syndrome. Am J Intellect Dev Disabil. 2010;115(1):54–75. http://www.ncbi.nlm.nih.gov/pubmed/20025359 CrossRefPubMedPubMedCentral

33.

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;41:237–44.CrossRefPubMed

34.

Wheeler A, Hatton D, Reichardt A, Bailey D. Correlates of maternal behaviours in mothers of children with fragile X syndrome. J Intellect Disabil Res. 2007;51(6):447–62. http://www.ncbi.nlm.nih.gov/pubmed/17493028 CrossRefPubMed

35.

Boer H. International handbook of applied research in intellectual disabilities. Br J Psychiatry Wiley. 2006;188:496. http://bjp.rcpsych.org/cgi/doi/10.1192/bjp.188.5.496 CrossRef

36.

Finestack LH, Richmond EK, Abbeduto L. Language development in individuals with fragile X syndrome. Top Lang Disord. 2009;29(2):133–48. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2854517/.

37.

Finestack LH, Sterling AM, Abbeduto L. Discriminating Down syndrome and fragile X syndrome based on language ability. J Child Lang. 2013;40(1):244–65. http://www.ncbi.nlm.nih.gov/pubmed/23217297 CrossRefPubMedPubMedCentral

38.

Channell MM, Thurman AJ, Kover ST, Abbeduto L. Patterns of change in nonverbal cognition in adolescents with Down syndrome. Res Dev Disabil. 2014;35:2933–41.CrossRefPubMedPubMedCentral

39.

Willemsen R, Smits A, Mohkamsing S, van Beerendonk H, de Haan A, de Vries B, et al. Rapid antibody test for diagnosing fragile X syndrome: a validation of the technique. Hum Genet. 1997;99(3):308–11. http://www.ncbi.nlm.nih.gov/pubmed/9050914 CrossRefPubMed

40.

Brown WT, Houck GE, Jeziorowska A, Levinson FN, Ding X, Dobkin C, et al. Rapid fragile X carrier screening and prenatal diagnosis using a nonradioactive PCR test. JAMA J Am Med Assoc. 1993;270(13):1569. http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.1993.03510130075034 CrossRef

41.

Derogatis LR. SCL-90. Administration, scoring and procedures manual-I for the R(evised) version. In: Derogatis LR, ed. Baltimore, John Hopkins University School of Medicine, Clinical Psychometrics Research Unit. 1977. https://www.pearsonclinical.com/psychology/products/100000645/symptom-checklist-90-revised-scl-90-r.html.

42.

Bengston VL, Black KD. Intergenerational relations and continuities in socialization. In P. Baltes, W.Schaie, editors. Life-span developmentalpsychology:Personality and socialization. New York: Academic Press; 1973. p. 207–34. http://linkinghub.elsevier.com/retrieve/pii/B9780120771509500150.

43.

Roid GH, Miller LJ. Leiter international performance scale–revised. Wood Dale: Stoelting; 1997.

44.

Williams KT. Expressive vocabulary test (EVT-2). Circle Pines: American Service; 1997.

45.

Hessl D, Nguyen DV, Green C, Chavez A, Tassone F, Hagerman RJ, et al. A solution to limitations of cognitive testing in children with intellectual disabilities: the case of fragile X syndrome. J Neurodev Disor. 2009;1(1):33–45. http://www.ncbi.nlm.nih.gov/pubmed/19865612 CrossRef

46.

Achenbach T, Rescorla LA. Manual for the ASEBA school-age forms & profiles. Burlington: University of Vermont, Research Center for Children, Youth, & Families; 2001.

47.

Kirchgessner CU, Warren ST, Willard HF. X inactivation of the FMR1 fragile X mental retardation gene. J Med Genet. 1995;32(12):925–9. http://www.ncbi.nlm.nih.gov/pubmed/8825916 CrossRefPubMedPubMedCentral

48.

Rajan-Babu I-S, Chong S. Molecular correlates and recent advancements in the diagnosis and screening of FMR1-related disorders. Genes (Basel) 2016;14;7(10):87. http://www.ncbi.nlm.nih.gov/pubmed/27754417.

49.

Hadd AG, Filipovic-Sadic S, Zhou L, Williams A, Latham GJ, Berry-Kravis E, et al. A methylation PCR method determines FMR1 activation ratios and differentiates premutation allele mosaicism in carrier siblings. Clin Epigenetics. 2016;8(1):130. http://www.ncbi.nlm.nih.gov/pubmed/27980694 CrossRefPubMedPubMedCentral

50.

Heine-Suñer D, Torres-Juan L, Morlà M, Busquets X, Barceló F, Picó G, et al. Fragile-X syndrome and skewed X-chromosome inactivation within a family: a female member with complete inactivation of the functional X chromosome. Am J Med Genet Part A. 2003;122A(2):108–14. http://doi.wiley.com/10.1002/ajmg.a.20160 CrossRefPubMed

51.

Talebizadeh Z, Bittel DC, Veatch OJ, Kibiryeva N, Butler MG. Brief report: non-random X chromosome inactivation in females with autism. J Autism Dev Disord. 2005;35(5):675–81. http://link.springer.com/10.1007/s10803-005-0011-z CrossRefPubMed

52.

Abrams MT, Reiss AL, Freund LS, Baumgardner TL, Chase GA, Denckla MB. Molecular-neurobehavioral associations in females with the fragile X full mutation. Am J Med Genet. 1994;51(4):317–27. http://www.ncbi.nlm.nih.gov/pubmed/7942994 CrossRefPubMed

53.

Stembalska A, Łaczmańska I, Gil J, Pesz KA. Fragile X syndrome in females—a familial case report and review of the literature. Dev period Med. 2016;20(2):99–104. from: http://www.ncbi.nlm.nih.gov/pubmed/27442693 PubMed

54.

Fisch GS, Carpenter N, Howard-Peebles PN, Holden JJA, Tarleton J, Simensen R. The course of cognitive-behavioral development in children with the FMR1 mutation, Williams-Beuren syndrome, and neurofibromatosis type 1: the effect of gender. Am J Med Genet Part A. 2010;152A(6) http://doi.wiley.com/10.1002/ajmg.a.33412.

55.

Van der Molen MJW, Huizinga M, Huizenga HM, Ridderinkhof KR, Van der Molen MW, Hamel BJC, et al. Profiling fragile X syndrome in males: strengths and weaknesses in cognitive abilities. Res Dev Disabil. 2010;31(2):426–39. http://www.ncbi.nlm.nih.gov/pubmed/19939624 CrossRefPubMed

56.

Sternberg RJ. Intelligence. Dialogues Clin Neurosci. 2012;14(1):19–27. http://www.ncbi.nlm.nih.gov/pubmed/22577301 PubMedPubMedCentral

57.

Tucker-Drob EM. Differentiation of cognitive abilities across the life span. Dev Psychol. 2009;45(4):1097–118. http://www.ncbi.nlm.nih.gov/pubmed/19586182 CrossRefPubMedPubMedCentral

58.

Wang JY, Hessl D, Iwahashi C, Cheung K, Schneider A, Hagerman RJ, et al. Influence of the fragile X mental retardation (FMR1) gene on the brain and working memory in men with normal FMR1 alleles. NeuroImage. 2013;65:288–98. http://www.ncbi.nlm.nih.gov/pubmed/23063447 CrossRefPubMed

59.

Greiff S, Wüstenberg S, Goetz T, Vainikainen M-P, Hautamäki J, Bornstein MH. A longitudinal study of higher-order thinking skills: working memory and fluid reasoning in childhood enhance complex problem solving in adolescence. Front Psychol. 2015;6(1060) http://www.ncbi.nlm.nih.gov/pubmed/26283992

60.

Lanfranchi S., Cornoldi C., Drigo S., Vianello R. Working memory in individuals with Fragile X syndrome. Child Neuropsychol. 2009;15 105–119. http://www.ncbi.nlm.nih.gov/pubmed/10.1080/09297040802112564.CrossRefPubMed

61.

Hoeft F, Hernandez A, Parthasarathy S, Watson CL, Hall SS, Reiss AL. Fronto-striatal dysfunction and potential compensatory mechanisms in male adolescents with fragile X syndrome. Hum Brain Mapp. 2007;28(6):543–54. http://www.ncbi.nlm.nih.gov/pubmed/17437282 CrossRefPubMed

62.

Siegel JJ, Chitwood RA, Ding JM, Payne C, Taylor W, Gray R, et al. Prefrontal cortex dysfunction in fragile X mice depends on the continued absence of fragile X mental retardation protein in the adult brain. J Neurosci. 2017;37(31):7305–17. http://www.jneurosci.org/lookup/doi/10.1523/JNEUROSCI.0571-17.2017 CrossRefPubMed

63.

Reiss AL, Dant CC. The behavioral neurogenetics of fragile X syndrome: analyzing gene–brain–behavior relationships in child developmental psychopathologies. Dev Psychopathol. 2003;15:927–68.CrossRefPubMed

64.

Hauser CT, Kover ST, Abbeduto L. Maternal well-being and child behavior in families with fragile X syndrome. Res Dev Disabil. 2014;35(10):2477–86. http://www.ncbi.nlm.nih.gov/pubmed/24984053 CrossRefPubMedPubMedCentral

65.

Bennett IM, Schott W, Krutikova S, Behrman JR. Maternal mental health, and child growth and development, in four low-income and middle-income countries. J Epidemiol Community Health. 2016;70(2):168–73. http://www.ncbi.nlm.nih.gov/pubmed/26359503 CrossRefPubMed

66.

Canadian Paediatric Society. Maternal depression and child development. Paediatr Child Health. 2004;9(8):575–98. http://www.ncbi.nlm.nih.gov/pubmed/19680490 CrossRef

67.

Johnston C, Hessl D, Blasey C, Eliez S, Erba H, Dyer-Friedman J, et al. Factors associated with parenting stress in mothers of children with fragile X syndrome. J Dev Behav Pediatr. 2003;24(4):267–75. http://www.ncbi.nlm.nih.gov/pubmed/12915799 CrossRefPubMed

68.

Hartley SL, Seltzer MM, Head L, Abbeduto L. Psychological well-being in fathers of adolescents and young adults with Down syndrome, fragile X syndrome, and autism. Fam Relat. 2012;61(2):327–42. http://doi.wiley.com/10.1111/j.1741-3729.2011.00693.x CrossRefPubMedPubMedCentral

69.

Olsson MB, Hwang CP. Depression in mothers and fathers of children with intellectual disability. J Intellect Disabil Res. 2001;45(6):535–43. http://doi.wiley.com/10.1046/j.1365-2788.2001.00372.x CrossRefPubMed

Title: Genetic and maternal predictors of cognitive and behavioral trajectories in females with fragile X syndrome
Authors: Laura del Hoyo Soriano
Angela John Thurman
Danielle Jenine Harvey
W. Ted Brown
Leonard Abbeduto
Publication date: 01-12-2018
Publisher: BioMed Central
Published in: Journal of Neurodevelopmental Disorders / Issue 1/2018
Print ISSN: 1866-1947
Electronic ISSN: 1866-1955
DOI: https://doi.org/10.1186/s11689-018-9240-2

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Genetic and maternal predictors of cognitive and behavioral trajectories in females with fragile X syndrome

Abstract

Background

Methods

Results

Conclusions

At a glance: The ONWARDS insulin icodec trials

Springer Medicine

Abstract

Background

Methods

Results

Conclusions

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