development of a behavioral outcome measure for rett syndrome (rettbe)

Conditions: Rett Syndrome

Summary: the overall purpose of this study is to develop a broad-based (i.e., multiple domains) behavioral outcome measure for children between the ages of 3-18 years with rett syndrome (rtt). the innovative approach of this proposal consists of integrating the process of developing a behavioral questionnaire to an ongoing large-scale data collection project. the natural history study of rett syndrome and related disorders (rtt5211) is a project that collects data on diverse aspects of the clinical evolution of individuals with rtt and related disorders. this project will serve as the basis for recruitment of subjects and it will also provide key demographic and clinical data for cohort characterization and for determining clinical relevance of the instrument (rettbe). an initial 100-subject cohort will allow for the testing with one rater of rettbe 1.0, a 50-item questionnaire formed from existing measures, a panel of clinicians and behavioral experts in rtt, and a focus group of parents and caregivers of children with rtt. scores on rettbe 1.0 will be statistically analyzed to determine their psychometric properties, including its content validity. items that do not meet psychometric standards (e.g., ceiling effect) will be eliminated. additional items will be added if the parental survey attached to rettbe 1.0 or clinician input suggests so. the resulting modified assessment, called rettbe 2.0, will be administered to a larger (validation) cohort of 300 participants. rettbe 2.0 will also be subjected to analysis of psychometric properties. rettbe 2.0 will also be administered to two raters per subject, in order to determine inter-rater reliability. in addition, these raters will be completing other behavioral and clinical measures for further evaluating the validity of rettbe 2.0 as well as for determining its clinical and functional significance. finally, the investigators will obtain input from a panel of clinicians (site pis and their designated clinicians) about content validity and clinical impact. the resulting version will be released as rettbe 3.0.

behavioral abnormalities, ranging from autistic symptoms to anxiety and mood lability, are now recognized as major clinical issues in rtt. these clinical manifestations are particularly problematic in higher functioning individuals since they seem to substantially affect their quality of life. moreover, novel drug treatments aiming at rtt's neurobiological mechanisms have the potential of targeting these abnormal behaviors. despite the recent emphasis on abnormal behaviors, little is known about their characteristics, severity, and impact. this is due, in part, to the paucity of behavioral measures compatible with the cognitive and motor impairments of rtt. the investigators currently have only one instrument with limited validation for delineating the range of behavioral abnormalities in rtt (the parent-rated rett syndrome behavioral questionnaire (rsbq)), which is a significant shortcoming to the implementation of treatment trials. moreover, there has not been a systematic approach for defining behavioral abnormalities in rtt (e.g., definition of mood abnormalities in rtt). these deficiencies have led the investigators to propose the creation of a broad-based behavioral outcome measure for use in rtt at different ages. due to the complexity of the clinical evolution of rtt and the relative limited knowledge on its adult period, the investigators will focus on children with rtt ages 3-18 years. the new measure will allow for standardized quantifications of behavioral outcomes in treatment trials and, eventually, in clinical practice. the investigators recognize that developing an instrument with strong psychometric properties is a major endeavor; therefore, the investigators conceived this project as a multi-stage process. the first stage, conducted with support of rettsyndrome.org, consisted of developing a prototype or first version of a behavioral questionnaire for parents of children with rtt (3-18 years), which the investigators have termed rettbe 1.0. the initial part of this study will test the psychometric properties (i.e., structure, content validity) of rettbe 1.0 with an initial cohort of 100 participants. this stage intends to transform rettbe 1.0 into a fully developed behavioral instrument within the framework of the natural history study (rtt5211). thus, in aim 1 the investigators will evaluate psychometrically rettbe 1.0 following, in part, previous studies including their examination of anxiety instruments and adaptation of the anxiety, depression and mood scale (adams) for rtt, and their adaptations of the aberrant behavior checklist-community (abc-c) for fragile x syndrome and down syndrome. in aim 1, they will also refine rettbe 1.0 by adding new "missing" items based on parental input or clinician (pis of sites involved) feedback. the resulting instrument, rettbe 2.0 will be tested in aim 2. testing of rettbe 2.0 will be carried out with a new (naïve) validation cohort of 300 subjects and two raters (preferentially both parents/caregivers, alternatively one teacher or therapist), to determine inter-rater reliability. one rater, preferentially a parent, will be asked to also complete three other behavioral measures (rsbq, adams, abc-c) for comparisons. scores for rettbe 2.0 will be analyzed in terms of psychometric properties, as performed for rettbe 1.0. however, in addition to structure (construct validity) and content validity, the investigators will also examine convergent and discriminant validity by correlating domain rettbe 2.0 scores with those of comparable and non-comparable domain scores of the rsbq, adams, and abc-c, respectively. finally, aim 3 will use data from the rtt5211 protocol to determine the effect of age on rettbe 2.0 scores and the clinical and functional significance of the measure. specifically, the investigators will examine score distributions throughout the age range, with special emphasis on early childhood (3-8 years), late childhood (8-12 years), and adolescence (\>12 years). clinical and functional relevance will be determined by correlations with instruments measuring multiple parameters of clinical severity, specifically, the cgi-s, clinical severity scale, and motor behavior assessment. relevance to quality of life will be evaluated by correlations with the child health questionnaire-parent form 50 (chq-pf50; child-oriented measure) and the short form (36) health survey (sf-36v2tm health survey; parent-oriented measure). all these instruments are components of the core rtt5211 protocol. finally, prior to its release as rettbe 3.0 (if psychometric properties are good-excellent), the investigators will obtain input from a panel of clinicians (site pis and their designated clinicians) about content validity and clinical impact.

Eligibility criteria:
inclusion criteria rettbe 1.0 initial cohort: * females 3 - 18 years * meets revised 2010 diagnostic criteria for classic or atypical rtt * post-regression status * documentation of positive mecp2 mutation * enrolled in the natural history study (rtt5211) rettbe 2.0 validation cohort: * meet above criteria * two raters are available and willing to evaluate the subject * must not have participated in rettbe 1.0 exclusion criteria both rettbe 1.0 and rettbe 2.0: * do not meet the above inclusion criteria * foster children * non-english speakers