Development of a Behavioral Outcome Measure for Rett Syndrome (RettBe)

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.

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