Anxiety-like behavior in Rett syndrome: characteristics and assessment by anxiety scales

Katherine V Barnes, Francesca R Coughlin, Heather M O'Leary, Natalie Bruck, Grace A Bazin, Emily B Beinecke, Alexandra C Walco, Nicole G Cantwell, Walter E Kaufmann, Katherine V Barnes, Francesca R Coughlin, Heather M O'Leary, Natalie Bruck, Grace A Bazin, Emily B Beinecke, Alexandra C Walco, Nicole G Cantwell, Walter E Kaufmann

Abstract

Background: Rett syndrome (RTT) is a severe neurodevelopmental disorder characterized by regression of language and motor skills, cognitive impairment, and frequent seizures. Although the diagnostic criteria focus on communication, motor impairments, and hand stereotypies, behavioral abnormalities are a prevalent and disabling component of the RTT phenotype. Among these problematic behaviors, anxiety is a prominent symptom. While the introduction of the Rett Syndrome Behavioral Questionnaire (RSBQ) represented a major advancement in the field, no systematic characterization of anxious behavior using the RSBQ or other standardized measures has been reported.

Methods: This study examined the profiles of anxious behavior in a sample of 74 girls with RTT, with a focus on identifying the instrument with the best psychometric properties in this population. The parent-rated RSBQ, Anxiety, Depression, and Mood Scale (ADAMS), and Aberrant Behavior Checklist-Community (ABC-C), two instruments previously employed in children with neurodevelopmental disorders, were analyzed in terms of score profiles, relationship with age and clinical severity, reliability, concurrent validity, and functional implications. The latter were determined by regression analyses with the Vineland Adaptive Behavior Scales-Second Edition (Vineland-II) and the Child Health Questionnaire (CHQ), a quality of life measure validated in RTT.

Results: We found that scores on anxiety subscales were intermediate in range with respect to other behavioral constructs measured by the RSBQ, ADAMS, and ABC-C. Age did not affect scores, and severity of general anxiety was inversely correlated with clinical severity. We demonstrated that the internal consistency of the anxiety-related subscales were among the highest. Test-retest and intra-rater reliability was superior for the ADAMS subscales. Convergent and discriminant validity were measured by inter-scale correlations, which showed the best profile for the social anxiety subscales. Of these, only the ADAMS Social Avoidance showed correlation with quality of life.

Conclusions: We conclude that anxiety-like behavior is a prominent component of RTT's behavioral phenotype, which affects predominantly children with less severe neurologic impairment and has functional consequences. Based on available data on standardized instruments, the ADAMS and in particular its Social Avoidance subscale has the best psychometric properties and functional correlates that make it suitable for clinical and research applications.

Keywords: Anxiety; Intellectual disabilities; Problematic behavior; Rett syndrome; Social avoidance.

References

    1. Laurvick CL, de Klerk N, Bower C, Christodoulou J, Ravine D, Ellaway C, et al. Rett syndrome in Australia: a review of the epidemiology. J Pediatr. 2006;148(3):347–352. doi: 10.1016/j.jpeds.2005.10.037.
    1. Amir RE, Van den Veyver IB, Wan M, Tran CQ, Francke U, Zoghbi HY. Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet. 1999;23(2):185–188. doi: 10.1038/13810.
    1. Cuddapah VA, Pillai RB, Shekar KV, Lane JB, Motil KJ, Skinner SA, et al. Methyl-CpG-binding protein 2 (MECP2) mutation type is associated with disease severity in Rett syndrome. J Med Genet. 2014;51(3):152–158. doi: 10.1136/jmedgenet-2013-102113.
    1. Neul JL, Lane JB, Lee HS, Geerts S, Barrish JO, Annese F, et al. Developmental delay in Rett syndrome: data from the natural history study. J Neurodev Disord. 2014;6(1):20. doi: 10.1186/1866-1955-6-20.
    1. Kaufmann WE, Johnston MV, Blue ME. MeCP2 expression and function during brain development: implications for Rett syndrome’s pathogenesis and clinical evolution. Brain Dev. 2005;27(Suppl 1):S77–S87. doi: 10.1016/j.braindev.2004.10.008.
    1. Gemelli T, Berton O, Nelson ED, Perrotti LI, Jaenisch R, Monteggia LM, et al. Postnatal loss of methyl-CpG binding protein 2 in the forebrain is sufficient to mediate behavioral aspects of Rett syndrome in mice. Biol Psychiatry. 2006;59(5):468–476. doi: 10.1016/j.biopsych.2005.07.025.
    1. Neul JL, Kaufmann WE, Glaze DG, Christodoulou J, Clarke AJ, Bahi-Buisson N, et al. Rett syndrome: revised diagnostic criteria and nomenclature. Ann Neurol. 2010;68(6):944–950. doi: 10.1002/ana.22124.
    1. Neul JL, Fang P, Barrish J, Lane J, Caeg EB, Smith EO, et al. Specific mutations in methyl-CpG-binding protein 2 confer different severity in Rett syndrome. Neurology. 2008;70(16):1313–1321. doi: 10.1212/01.wnl.0000291011.54508.aa.
    1. Bebbington A, Anderson A, Ravine D, Fyfe S, Pineda M, de Klerk N, et al. Investigating genotype-phenotype relationships in Rett syndrome using an international data set. Neurology. 2008;70(11):868–875. doi: 10.1212/.
    1. Hagberg B. Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil Res Rev. 2002;8(2):61–65. doi: 10.1002/mrdd.10020.
    1. Marschik PB, Kaufmann WE, Sigafoos J, Wolin T, Zhang D, Bartl-Pokorny KD, et al. Changing the perspective on early development of Rett syndrome. Res Dev Disabil. 2013;34(4):1236–1239. doi: 10.1016/j.ridd.2013.01.014.
    1. Anderson A, Wong K, Jacoby P, Downs J, Leonard H. Twenty years of surveillance in Rett syndrome: what does this tell us? Orphanet J Rare Dis. 2014;9:87. doi: 10.1186/1750-1172-9-87.
    1. Kaufmann WE, Tierney E, Rohde CA, Suarez-Pedraza MC, Clarke MA, Salorio CF, et al. Social impairments in Rett syndrome: characteristics and relationship with clinical severity. J Intellect Disabil Res. 2012;56(3):233–247. doi: 10.1111/j.1365-2788.2011.01404.x.
    1. Mount RH, Hastings RP, Reilly S, Cass H, Charman T, et al. Behaviour problems in adult women with Rett syndrome. J Intellect Disabil Res. 2002;46(Pt 8):619–624. doi: 10.1046/j.1365-2788.2002.00442.x.
    1. Sansom D, Krishnan VH, Corbett J, Kerr A. Emotional and behavioural aspects of Rett syndrome. Dev Med Child Neurol. 1993;35(4):340–345. doi: 10.1111/j.1469-8749.1993.tb11646.x.
    1. Cianfaglione R, Clarke A, Kerr M, Hastings RP, Oliver C, Moss J, et al. A national survey of Rett syndrome: behavioural characteristics. J Neurodev Disord. 2015;7(1):11. doi: 10.1186/s11689-015-9104-y.
    1. Banerjee A, Castro J, Sur M. Rett syndrome: genes, synapses, circuits, and therapeutics. Front Psychiatry. 2012;3:34. doi: 10.3389/fpsyt.2012.00034.
    1. Moretti P, Bouwknecht JA, Teague R, Paylor R, Zoghbi HY. Abnormalities of social interactions and home-cage behavior in a mouse model of Rett syndrome. Hum Mol Genet. 2005;14(2):205–220. doi: 10.1093/hmg/ddi016.
    1. Shahbazian M, Young J, Yuva-Paylor L, Spencer C, Antalffy B, Noebels J, et al. Mice with truncated MeCP2 recapitulate many Rett syndrome features and display hyperacetylation of histone H3. Neuron. 2002;35(2):243–254. doi: 10.1016/S0896-6273(02)00768-7.
    1. Hagberg B, Aicardi J, Dias K, Ramos O. A progressive syndrome of autism, dementia, ataxia, and loss of purposeful hand use in girls: Rett’s syndrome: report of 35 cases. Ann Neurol. 1983;14(4):471–479. doi: 10.1002/ana.410140412.
    1. Percy AK, Zoghbi HY, Lewis KR, Jankovic J. Rett syndrome: qualitative and quantitative differentiation from autism. J Child Neurol. 1988;3(Suppl):S65–S67. doi: 10.1177/088307388800300112.
    1. Zappella M. Rett syndrome: a significant proportion of girls affected by autistic behavior. Brain Dev. 1985;7(3):307–312. doi: 10.1016/S0387-7604(85)80034-6.
    1. Wulffaert J, Van Berckelaer-Onnes IA, Scholte EM. Autistic disorder symptoms in Rett syndrome. Autism. 2009;13(6):567–581. doi: 10.1177/1362361309338184.
    1. Mount RH, Charman T, Hastings RP, Reilly S, Cass H. The Rett Syndrome Behaviour Questionnaire (RSBQ): refining the behavioural phenotype of Rett syndrome. J Child Psychol Psychiatry. 2002;43(8):1099–1110. doi: 10.1111/1469-7610.00236.
    1. Robertson L, Hall SE, Jacoby P, Ellaway C, de Klerk N, Leonard H. The association between behavior and genotype in Rett syndrome using the Australian Rett Syndrome Database. Am J Med Genet B Neuropsychiatr Genet. 2006;141B(2):177–183. doi: 10.1002/ajmg.b.30270.
    1. Coleman M, Brubaker J, Hunter K, Smith G. Rett syndrome: a survey of North American patients. J Ment Defic Res. 1988;32(Pt 2):117–124.
    1. Cass H, Reilly S, Owen L, Wisbeach A, Weekes L, Slonims V, et al. Findings from a multidisciplinary clinical case series of females with Rett syndrome. Dev Med Child Neurol. 2003;45(5):325–337. doi: 10.1111/j.1469-8749.2003.tb00404.x.
    1. Halbach NS, Smeets EE, Schrander-Stumpel CT, van Schrojenstein Lantman de Valk HH, Maaskant MA, Curfs LM. Aging in people with specific genetic syndromes: Rett syndrome. Am J Med Genet A. 2008;146A(15):1925–1932. doi: 10.1002/ajmg.a.32361.
    1. Naidu S, Murphy M, Moser HW, Rett A. Rett syndrome—natural history in 70 cases. Am J Med Genet Suppl. 1986;1:61–72. doi: 10.1002/ajmg.1320250507.
    1. Cordeiro L, Ballinger E, Hagerman R, Hessl D. Clinical assessment of DSM-IV anxiety disorders in fragile X syndrome: prevalence and characterization. J Neurodev Disord. 2011;3(1):57–67. doi: 10.1007/s11689-010-9067-y.
    1. Esbensen AJ, Rojahn J, Aman MG, Ruedrich S. Reliability and validity of an assessment instrument for anxiety, depression, and mood among individuals with mental retardation. J Autism Dev Disord. 2003;33(6):617–629. doi: 10.1023/B:JADD.0000005999.27178.55.
    1. Rojahn J, Rowe EW, Kasdan S, Moore L, van Ingen DJ. Psychometric properties of the Aberrant Behavior Checklist, the Anxiety, Depression and Mood Scale, the Assessment of Dual Diagnosis and the Social Performance Survey Schedule in adults with intellectual disabilities. Res Dev Disabil. 2011;32(6):2309–2320. doi: 10.1016/j.ridd.2011.07.035.
    1. Khwaja OS, Ho E, Barnes KV, O'Leary HM, Pereira L.M, Finkelstein Y, et al. Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A. 2014;111(12):4596–4601. doi: 10.1073/pnas.1311141111.
    1. McManis MH, Kagan J, Snidman NC, Woodward SA. EEG asymmetry, power, and temperament in children. Dev Psychobiol. 2002;41(2):169–177. doi: 10.1002/dev.10053.
    1. Castro J, Garcia RI, Kwok S, Banerjee A, Petravicz J, Woodson J, et al. Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome. Proc Natl Acad Sci U S A. 2014;111(27):9941–9946. doi: 10.1073/pnas.1311685111.
    1. Aman MG, Singh NN. Aberrant Behavior Checklist-Community Manual. NY: Slosson Educational publications: E Aurora; 1986.
    1. Budimirovic DB, Bukelis I, Cox C, Gray RM, Tierney E, Kaufmann WE. Autism spectrum disorder in Fragile X syndrome: differential contribution of adaptive socialization and social withdrawal. Am J Med Genet A. 2006;140A(17):1814–1826. doi: 10.1002/ajmg.a.31405.
    1. Sansone SM, Widaman KF, Hall SS, Reiss AL, Lightbody A, Kaufmann WE, et al. Psychometric study of the Aberrant Behavior Checklist in Fragile X Syndrome and implications for targeted treatment. J Autism Dev Disord. 2012;42(7):1377–1392. doi: 10.1007/s10803-011-1370-2.
    1. Ji NY, Capone GT, Kaufmann WE. Autism spectrum disorder in Down syndrome: cluster analysis of Aberrant Behaviour Checklist data supports diagnosis. J Intellect Disabil Res. 2011;55(11):1064–1077. doi: 10.1111/j.1365-2788.2011.01465.x.
    1. McCracken JT, McGough J, Shah B, Cronin P, Hong D, Aman MG, et al. Risperidone in children with autism and serious behavioral problems. N Engl J Med. 2002;347(5):314–321. doi: 10.1056/NEJMoa013171.
    1. Monros E, Armstrong J, Aibar E, Poo P, Canos I, Pineda M. Rett syndrome in Spain: mutation analysis and clinical correlations. Brain Dev. 2001;23(Suppl 1):S251–S253. doi: 10.1016/S0387-7604(01)00374-6.
    1. Sparrow SS, Cicchetti DV, Balla DA. Vineland Adaptive Behavior Scales: Second Edition (Vineland II) Livonia: Pearson Assessments; 2005.
    1. Berry-Kravis E, Krause SE, Block SS, Guter S, Wuu J, Leurgans S, et al. Effect of CX516, an AMPA-modulating compound, on cognition and behavior in fragile X syndrome: a controlled trial. J Child Adolesc Psychopharmacol. 2006;16(5):525–540. doi: 10.1089/cap.2006.16.525.
    1. Perry A, Flanagan HE, Dunn Geier J, Freeman NL. Brief report: the Vineland Adaptive Behavior Scales in young children with autism spectrum disorders at different cognitive levels. J Autism Dev Disord. 2009;39(7):1066–1078. doi: 10.1007/s10803-009-0704-9.
    1. Duker PC, van Driel S, van de Bercken J. Communication profiles of individuals with Down’s syndrome, Angelman syndrome and pervasive developmental disorder. J Intellect Disabil Res. 2002;46(Pt 1):35–40. doi: 10.1046/j.1365-2788.2002.00355.x.
    1. Fidler DJ, Hepburn S, Rogers S. Early learning and adaptive behaviour in toddlers with Down syndrome: evidence for an emerging behavioural phenotype? Downs Syndr Res Pract. 2006;9(3):37–44. doi: 10.3104/reports.297.
    1. Waters E, Davis E, Nicolas C, Wake M, Lo SK. The impact of childhood conditions and concurrent morbidities on child health and well-being. Child Care Health Dev. 2008;34(4):418–429. doi: 10.1111/j.1365-2214.2008.00825.x.
    1. Koscik RL, Douglas JA, Zaremba K, Rock MJ, Splaingard ML, Laxova A, et al. Quality of life of children with cystic fibrosis. J Pediatr. 2005;147(3 Suppl):S64–S68. doi: 10.1016/j.jpeds.2005.09.001.
    1. Kennedy CH, Juarez AP, Becker A, Greenslade K, Harvey MT, Sullivan C, et al. Children with severe developmental disabilities and behavioral disorders have increased special healthcare needs. Dev Med Child Neurol. 2007;49(12):926–930. doi: 10.1111/j.1469-8749.2007.00926.x.
    1. Lane JB, Lee HS, Smith LW, Cheng P, Percy AK, Glaze DG, et al. Clinical severity and quality of life in children and adolescents with Rett syndrome. Neurology. 2011;77(20):1812–1818. doi: 10.1212/WNL.0b013e3182377dd2.
    1. Crawford JR, Garthwaite PH. Percentiles please: the case for expressing neuropsychological test scores and accompanying confidence limits as percentile ranks. Clin Neuropsychol. 2009;23(2):193–204. doi: 10.1080/13854040801968450.
    1. Kaufmann WE, Cortell R, Kau AS, Bukelis I, Tierney E, Gray RM, et al. Autism spectrum disorder in fragile X syndrome: communication, social interaction, and specific behaviors. Am J Med Genet A. 2004;129A(3):225–234. doi: 10.1002/ajmg.a.30229.
    1. Cortina JM. What is coefficient alpha? An examination of theory and applications. J Appl Psychol. 1993;78:98–104. doi: 10.1037/0021-9010.78.1.98.
    1. Shrout PE, Fleiss JL. Intraclass correlations: uses in assessing rater reliability. Psychol Bull. 1979;86(2):420–428. doi: 10.1037/0033-2909.86.2.420.
    1. Koch GG. Intraclass correlation coefficient. In: Samuel K, Norman L, editors. Johnson Encyclopedia of Statistical Sciences. New York: John Wiley & Sons; 1982. pp. 213–217.
    1. Wheeler A, Raspa M, Bann C, Bishop E, Hessl D, Sacco P, et al. Anxiety, attention problems, hyperactivity, and the Aberrant Behavior Checklist in fragile X syndrome. Am J Med Genet A. 2014;164A(1):141–155. doi: 10.1002/ajmg.a.36232.
    1. Mount RH, Charman T, Hastings RP, Reilly S, Cass H. Features of autism in Rett syndrome and severe mental retardation. J Autism Dev Disord. 2003;33(4):435–442. doi: 10.1023/A:1025066913283.
    1. Sparrow SS, Cicchetti DV. Diagnostic uses of the Vineland Adaptive Behavior Scales. J Pediatr Psychol. 1985;10(2):215–225. doi: 10.1093/jpepsy/10.2.215.
    1. Fyfe S, Downs J, McIlroy O, Burford B, Lister J, Reilly S, et al. Development of a video-based evaluation tool in Rett syndrome. J Autism Dev Disord. 2007;37(9):1636–1646. doi: 10.1007/s10803-006-0293-9.

Source: PubMed

Sponsors and Collaborators

Medical Conditions

Drug Interventions

3
Subscribe