1. RTT5214 Protocol Development of RettBe 2016 Rettsyndrome.org Research Symposium Natural History Study Chicago, June 24, 2016 Walter E. Kaufmann Center for Translational Research Greenwood Genetic Center Boston Children’s Hospital

2. Disclosures Consultant to Neuren, Edison, Newron, EryDel, Marinus, and GW Pharmaceuticals. Research support from Ipsen and Eloxx. Member of the Neurodevelopmental Disorders Work Group, Diagnostic and Statistical Manual of Mental Disorders-Fifth Edition (DSM-5).

3. RTT5214: RettBe Behavioral problems are common in RTT Main behavioral domains/syndromes in intellectual disability 1.Disruptive/aggressive/self-injurious behavior 2.ADHD-like (attentional difficulties, hyperactivity, impulsivity) 3.Anxiety-like 4.Mood abnormalities 5.Autistic behavior (social communication/interaction during regression) 6.Stereotypic/repetitive/OCD-like

4. RTT5214: RettBe Behavioral problems are difficult to diagnose and measure in RTT A new measure for the range of behavioral abnormalities in RTT 1.A general problem in intellectual disability. 2.In RTT, there are additional communication and motor impairments. 3.The instrument has to be multi-dimensional and RTT-specific because appearance of concurrent behaviors is different. 4. The measure is needed for clinic visits and research (intervention studies). 5. The only available multi-dimensional scale in RTT, the RSBQ, has important limitations (Barnes et al. J Neurodevelop Disord 7:30, 2015).

5. Bases: 1.Survey of parents 2.Consultation with clinicians 3.Consultation with behavioral researchers 4.Examination of existing measures: RSBQ, ABC-C, ADAMS. RettBe prototype (RettBe 1.0): 9 domains and 50 items: 1.Emotional behavior (non-anxiety): 10 items 2.Anxiety/fear: 2 items 3.Social behavior: 4 items 4.Attentional difficulties: 5 items 5.Sensory stimulation: 2 items 6.Stereotypic repetitive/motor behaviors: 13 items 7.Restricted motor behaviors: 6 items 8.Breathing problems: 4 items 9.Maladaptive behaviors: 4 items Target population: 400 girls with RTT and a MECP2 mutation, between 3-18 years. Developing RettBe RTT5214: RettBe

6. Example of RettBe 1.0 items & scoring Developing RettBe RTT5214: RettBe

7. Steps 1.RettBe 1.0 tested by 100 families. One rater (caregiver) will respond preferentially online. Child enrolled in NHS (all child and family history data available). 2.Psychometric evaluation of responses to RettBe 1.0: range of scores, factor analysis, internal consistency. 3.Reconfiguration of RettBe 1.0, potentially deleting and adding items, and refactoring resulting in RettBe 2.0 Developing RettBe RTT5214: RettBe

8. Steps 4. RettBe 2.0 tested by 300 different families. Two raters (both caregivers, or teacher/therapist) will respond preferentially online. Child enrolled in NHS (all child and family history data available). 5. Psychometric evaluation of responses: range of scores, internal consistency, inter-rater reliability, convergent and discriminant validity with RSBQ, ABC-C and ADAMS. 6. Relationship between RettBe 2.0 scores and age, clinical severity, and quality of life (child- and parent-oriented surveys). 7. Reconfiguration of RettBe 2.0, if needed. 8. Release of RettBe 3.0 to the RTT and NDD communities. Developing RettBe RTT5214: RettBe