Family as a Context for Child Development: Mothers with the FMR1 Premutation and Their Children with Fragile X Syndrome

Abstract

Fragile X syndrome (FXS) is a genetic disorder caused by changes of the FMR1 gene that is passed along among families. A range of developmental processes may be impacted with wide variation in abilities across individuals with FXS. Mothers of children with FXS are often carriers of a “premutation” expansion on the FMR1 gene, which is associated with its own clinical phenotype. These maternal features may increase individual and family vulnerabilities, including increased risk for depression and anxiety disorders and difficulties in social and cognitive ability. These characteristics may worsen with age, and potentially interact with a child's challenging behaviors and with family dynamics. Thus, families of children with FXS may experience unique challenges related to genetic risk, manifested across both children and parents, that should be considered in therapeutic planning to optimize outcomes for children and their families. In this article, we review core features of the FMR1 premutation as expressed in mothers and aspects of the family environment that interface with developmental outcomes of children with FXS. Recommendations for family-centered support services are discussed.

Keywords

fragile X premutation - fragile X syndrome - fragile X carriers - mother–child associations

Disclosures

The authors have no relevant financial or nonfinancial relationships to disclose.

Publikationsverlauf

Artikel online veröffentlicht:
26. Juli 2021

• References

• 1 Hunter J, Rivero-Arias O, Angelov A, Kim E, Fotheringham I, Leal J. Epidemiology of fragile X syndrome: a systematic review and meta-analysis. Am J Med Genet A 2014; 164A [phone]
• 2 Rousseau F, Heitz D, Tarleton J. et al. A multicenter study on genotype-phenotype correlations in the fragile X syndrome, using direct diagnosis with probe StB12.3: the first 2,253 cases. Am J Hum Genet 1994; 55 (02) 225-237
• 3 Abbeduto L, Thurman AJ, McDuffie A. et al. ASD comorbidity in fragile X syndrome: symptom profile and predictors of symptom severity in adolescent and young adult males. J Autism Dev Disord 2019; 49 (03) 960-977
• 4 Clifford S, Dissanayake C, Bui QM, Huggins R, Taylor AK, Loesch DZ. Autism spectrum phenotype in males and females with fragile X full mutation and premutation. J Autism Dev Disord 2007; 37 (04) 738-747
• 5 Haebig E, Sterling A, Barton-Hulsey A, Friedman L. Rates and predictors of co-occurring autism spectrum disorder in boys with fragile X syndrome. Autism Dev Lang Impair 2020; ; (epub ahead of print)
• 6 Harris SW, Hessl D, Goodlin-Jones B. et al. Autism profiles of males with fragile X syndrome. Am J Ment Retard 2008; 113 (06) 427-438
• 7 Hagerman RJ, Protic D, Rajaratnam A, Salcedo-Arellano MJ, Aydin EY, Schneider A. Fragile X-associated neuropsychiatric disorders (FXAND). Front Psychiatry 2018; 9: 564
• 8 Klusek J, Martin GE, Losh M. Physiological arousal in autism and fragile X syndrome: group comparisons and links with pragmatic language. Am J Intellect Dev Disabil 2013; 118 (06) 475-495
• 9 Ezell J, Hogan A, Fairchild A. et al. Prevalence and predictors of anxiety disorders in adolescent and adult males with autism spectrum disorder and fragile X syndrome. J Autism Dev Disord 2019; 49 (03) 1131-1141
• 10 Schmitt LM, Shaffer RC, Hessl D, Erickson C. Executive function in fragile X syndrome: a systematic review. Brain Sci 2019; 9 (01) E15
• 11 Price J, Roberts J, Vandergrift N, Martin G. Language comprehension in boys with fragile X syndrome and boys with Down syndrome. J Intellect Disabil Res 2007; 51 (Pt 4): 318-326
• 12 Roberts JE, Mirrett P, Anderson K, Burchinal M, Neebe E. Early communication, symbolic behavior, and social profiles of young males with fragile X syndrome. Am J Speech Lang Pathol 2002; 11: 295-304
• 13 Klusek J, Martin GE, Losh M. A comparison of pragmatic language in boys with autism and fragile X syndrome. J Speech Lang Hear Res 2014; 57 (05) 1692-1707
• 14 Adlof SM, Klusek J, Shinkareva SV, Robinson ML, Roberts JE. Phonological awareness and reading in boys with fragile X syndrome. J Child Psychol Psychiatry 2015; 56 (01) 30-39
• 15 Finestack LH, Abbeduto L. Expressive language profiles of verbally expressive adolescents and young adults with Down syndrome or fragile X syndrome. J Speech Lang Hear Res 2010; 53 (05) 1334-1348
• 16 Barnes E, Roberts J, Long SH. et al. Phonological accuracy and intelligibility in connected speech of boys with fragile X syndrome or Down syndrome. J Speech Lang Hear Res 2009; 52 (04) 1048-1061
• 17 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 (05) 905-914
• 18 Johnson CJ, Beitchman JH, Brownlie EB. Twenty-year follow-up of children with and without speech-language impairments: family, educational, occupational, and quality of life outcomes. Am J Speech Lang Pathol 2010; 19 (01) 51-65
• 19 Hersh JH, Saul RA, Saal HM. et al; Committee on Genetics. Health supervision for children with fragile X syndrome. Pediatrics 2011; 127 (05) 994-1006
• 20 Tassone F, Hagerman RJ, Chamberlain WD, Hagerman PJ. Transcription of the FMR1 gene in individuals with fragile X syndrome. Am J Med Genet 2000; 97 (03) 195-203
• 21 Hagerman RJ, Berry-Kravis E, Hazlett HC. et al. Fragile X syndrome. Nat Rev Dis Primers 2017; 3 (01) 17065
• 22 Hagerman PJ, Hagerman RJ. Fragile X syndrome. In: Howlin P, Udwin O. eds. Cambridge Child and Adolescent Psychiatry: Outcomes in Neurodevelopmental and Genetic Disorders. Cambridge, MA: Cambridge University Press; 2002: 198-219
• 23 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 2012; 159B [phone]
• 24 Nolin SL, Lewis III FA, Ye LL. et al. Familial transmission of the FMR1 CGG repeat. Am J Hum Genet 1996; 59 (06) 1252-1261
• 25 Sullivan AK, Marcus M, Epstein MP. et al. Association of FMR1 repeat size with ovarian dysfunction. Hum Reprod 2005; 20 (02) 402-412
• 26 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 (10) 1359-1362
• 27 Del Hoyo Soriano L, Thurman AJ, Harvey DJ, Ted Brown W, Abbeduto L. Genetic and maternal predictors of cognitive and behavioral trajectories in females with fragile X syndrome. J Neurodev Disord 2018; 10 (01) 22
• 28 Klusek J, McGrath SE, Abbeduto L, Roberts JE. Pragmatic language features of mothers with the FMR1 premutation are associated with the language outcomes of adolescents and young adults with fragile X syndrome. J Speech Lang Hear Res 2016; 59 (01) 49-61
• 29 Losh M, Klusek J, Martin GE, Sideris J, Parlier M, Piven J. 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 [phone]
• 30 Sterling AM, Mailick M, Greenberg J, Warren SF, Brady N. Language dysfluencies in females with the FMR1 premutation. Brain Cogn 2013; 82 (01) 84-89
• 31 Bailey Jr DB, Sideris J, Roberts J, Hatton D. Child and genetic variables associated with maternal adaptation to fragile X syndrome: a multidimensional analysis. Am J Med Genet A 2008; 146A [phone]
• 32 Roberts JE, Bailey Jr DB, Mankowski J. et al. Mood and anxiety disorders in females with the FMR1 premutation. Am J Med Genet B Neuropsychiatr Genet 2009; 150B [phone]
• 33 Roberts JE, Tonnsen BL, McCary LM, Ford AL, Golden RN, Bailey Jr DB. Trajectory and predictors of depression and anxiety disorders in mothers with the FMR1 premutation. Biol Psychiatry 2016; 79 (10) 850-857
• 34 Kenna HA, Tartter M, Hall SS. et al. High rates of comorbid depressive and anxiety disorders among women with premutation of the FMR1 gene. Am J Med Genet B Neuropsychiatr Genet 2013; 162B [phone]
• 35 Seltzer MM, Barker ET, Greenberg JS, Hong J, Coe C, Almeida D. Differential sensitivity to life stress in FMR1 premutation carrier mothers of children with fragile X syndrome. Health Psychol 2012; 31 (05) 612-622
• 36 Hessl D, Dyer-Friedman J, Glaser B. 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 (05) E88
• 37 Greenberg J, Seltzer M, Baker J. et al. Family environment and behavior problems in children, adolescents, and adults with fragile X syndrome. Am J Intellect Dev Disabil 2012; 117 (04) 331-346
• 38 Klusek J, Fairchild AJ, Roberts JE. Vagal tone as a putative mechanism for pragmatic competence: an investigation of carriers of the FMR1 premutation. J Autism Dev Disord 2019; 49 (01) 197-208
• 39 Losh M, Martin GE, Klusek J, Hogan-Brown AL, Sideris J. Social communication and theory of mind in boys with autism and fragile x syndrome. Front Psychol 2012; 3: 266
• 40 Sameroff AJ, Fiese BH. Handbook of Early Childhood Intervention. 2nd ed.. Cambridge, MA: Cambridge University Press; 2000
• 41 Brady NC, Fleming K, Bredin-Oja SL, Fielding-Gebhardt H, Warren SF. Language development from early childhood to adolescence in youths with fragile X syndrome. J Speech Lang Hear Res 2020; 63 (11) 3727-3742
• 42 Ingersoll B, Gergans S. The effect of a parent-implemented imitation intervention on spontaneous imitation skills in young children with autism. Res Dev Disabil 2007; 28 (02) 163-175
• 43 Sterling AM, Warren SF, Brady N, Fleming K. Influences on maternal responsivity in mothers of children with fragile X syndrome. Am J Intellect Dev Disabil 2013; 118 (04) 310-326
• 44 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 (01) 54-75
• 45 Moser C, Mattie L, Abbeduto L, Klusek J. The FMR1 premutation phenotype and mother-youth synchrony in fragile X syndrome. Am J Intellect Disabil. In press
• 46 Klusek J, Thurman AJ, Abbeduto L. Maternal pragmatic language difficulties in the FMR1 premutation and the broad autism phenotype: associations with individual and family outcomes. J Autism Dev Disord 2021; ; (epub ahead of print)
• 47 Semenza C, Bonollo S, Polli R. et al. Genetics and mathematics: FMR1 premutation female carriers. Neuropsychologia 2012; 50 (14) 3757-3763
• 48 Lachiewicz AM, Dawson DV, Spiridigliozzi GA, McConkie-Rosell A. Arithmetic difficulties in females with the fragile X premutation. Am J Med Genet A 2006; 140 (07) 665-672
• 49 Goodrich-Hunsaker NJ, Wong LM, McLennan Y. et al. Young adult female fragile X premutation carriers show age- and genetically-modulated cognitive impairments. Brain Cogn 2011; 75 (03) 255-260
• 50 Goodrich-Hunsaker NJ, Wong LM, McLennan Y. et al. Adult female fragile X premutation carriers exhibit age- and CGG repeat length-related impairments on an attentionally based enumeration task. Front Hum Neurosci 2011; 5: 63
• 51 Kraan CM, Hocking DR, Bradshaw JL. et al. Neurobehavioural evidence for the involvement of the FMR1 gene in female carriers of fragile X syndrome. Neurosci Biobehav Rev 2013; 37 (03) 522-547
• 52 Hunter JE, Allen EG, Abramowitz A. et al. No evidence for a difference in neuropsychological profile among carriers and noncarriers of the FMR1 premutation in adults under the age of 50. Am J Hum Genet 2008; 83 (06) 692-702
• 53 Hunter JE, Epstein MP, Tinker SW, Abramowitz A, Sherman SL. The FMR1 premutation and attention-deficit hyperactivity disorder (ADHD): evidence for a complex inheritance. Behav Genet 2012; 42 (03) 415-422
• 54 Hashimoto R, Backer KC, Tassone F, Hagerman RJ, Rivera SM. An fMRI study of the prefrontal activity during the performance of a working memory task in premutation carriers of the fragile X mental retardation 1 gene with and without fragile X-associated tremor/ataxia syndrome (FXTAS). J Psychiatr Res 2011; 45 (01) 36-43
• 55 Moser C, Schmitt L, Schmidt J, Fairchild A, Klusek J. Response inhibition deficits in women with the FMR1 premutation are associated with age and fall risk. Brain Cogn 2021; 148: 105675
• 56 Klusek J, Hong J, Sterling A, Berry-Kravis E, Mailick MR. Inhibition deficits are modulated by age and CGG repeat length in carriers of the FMR1 premutation allele who are mothers of children with fragile X syndrome. Brain Cogn 2020; 139: 105511
• 57 Kraan CM, Hocking DR, Georgiou-Karistianis N. et al. Impaired response inhibition is associated with self-reported symptoms of depression, anxiety, and ADHD in female FMR1 premutation carriers. Am J Med Genet B Neuropsychiatr Genet 2014; 165B (01) 41-51
• 58 Shelton AL, Cornish KM, Kraan CM, Lozano R, Bui M, Fielding J. Executive dysfunction in female FMR1 premutation carriers. Cerebellum 2016; 15 (05) 565-569
• 59 Klusek J, Porter A, Abbeduto L. et al. Curvilinear association between language disfluency and FMR1 CGG repeat size across the normal, intermediate, and premutation range. Front Genet 2018; 9: 344
• 60 Hasher L, Zacks RT. Working memory, comprehension, and aging: a review and a new view. Psychol Learn 1988; 22: 193-225
• 61 Bredin-Oja SL, Warren SF, Swinburne Romine RE, Fleming KK, Brady N, Berry-Kravis E. Word retrieval difficulty in adult females with the FMR1 premutation: changes over time and across contexts. Brain Cogn 2021; 148: 105694
• 62 Seltzer MM, Abbeduto L, Greenberg JS, Almeida D, Hong J, Witt W. Biomarkers in the study of families of children with developmental disabilities. Int Rev Res Ment Retard 2009; 37: 213-249
• 63 Bailey Jr DB, Raspa M, Bishop E, Holiday D. No change in the age of diagnosis for fragile x syndrome: findings from a national parent survey. Pediatrics 2009; 124 (02) 527-533
• 64 McDuffie A, Machalicek W, Bullard L. et al. A spoken-language intervention for school-aged boys with fragile X syndrome. Am J Intellect Dev Disabil 2016; 121 (03) 236-265
• 65 Thurman AJ, Potter LA, Kim K. et al. Controlled trial of lovastatin combined with an open-label treatment of a parent-implemented language intervention in youth with fragile X syndrome. J Neurodev Disord 2020; 12 (01) 12
• 66 McDuffie A, Banasik A, Bullard L. et al. Distance delivery of a spoken language intervention for school-aged and adolescent boys with fragile X syndrome. Dev Neurorehabil 2018; 21 (01) 48-63
• 67 Hartley SL, Seltzer MM, Raspa M, Olmstead M, Bishop E, Bailey DB. Exploring the adult life of men and women with fragile X syndrome: results from a national survey. Am J Intellect Dev Disabil 2011; 116 (01) 16-35
• 68 Brady NC, Bruce S, Goldman A. et al. Communication services and supports for individuals with severe disabilities: guidance for assessment and intervention. Am J Intellect Dev Disabil 2016; 121 (02) 121-138
• 69 National Joint Committee for the Communication Needs of Persons With Severe Disabilities, Access to communication services and supports: Concerns regarding the application of restrictive “eligibility” policies [Technical Report]. American Speech-Language and Hearing Association. Published 2002at: www.asha.org/policy
• 70 Martin GE, Ausderau KK, Raspa M, Bishop E, Mallya U, Bailey Jr DB. Therapy service use among individuals with fragile X syndrome: findings from a US parent survey. J Intellect Disabil Res 2013; 57 (09) 837-849
• 71 Roberts JE, Ezell JE, Fairchild AJ. et al. Biobehavioral composite of social aspects of anxiety in young adults with fragile X syndrome contrasted to autism spectrum disorder. Am J Med Genet B Neuropsychiatr Genet 2018; 177 (07) 665-675
• 72 Mailick MR, Hong J, Greenberg J, Smith L, Sherman S. Curvilinear association of CGG repeats and age at menopause in women with FMR1 premutation expansions. Am J Med Genet B Neuropsychiatr Genet 2014; 165B [phone]