Reverse Rett

Abstract Purpose:Rett syndrome is a severe neurodevelopmental disorder that affects about 1 in 10,000 females. Clinical trials of disease modifying therapies are on the rise, but there are few psychometrically sound caregiver-reported outcome measures available to assess treatment benefit. We report on a new caregiver-reported outcome measure, the Rett Caregiver Assessment of Symptom Severity (RCASS).Methods:Using data from the Rett Natural History Study (n=649), we examined the factor structure, using both exploratory and confirmatory factor analysis, and the reliability and validity of the RCASS.Results:The four-factor model had the best overall fit, which covered movement, communication, behavior, and Rett-specific symptoms. The RCASS had moderate internal consistency. Strong face validity was found with age and mutation type, and criterion validity was established with other similar measures, including the Revised Motor-Behavior Assessment Scale, Clinical Severity Scale, Clinical Global Impression Scale, and the Child Health Questionnaire.Conclusion:These data provide initial evidence that the RCASS is a viable caregiver-outcome measure for use in clinical trials in Rett syndrome. Future work to assess sensitivity to change and other measures of reliability, such as test-retest and inter-rater agreement, are needed.

Rett syndrome is the familiar expression of a profoundly disabling disorder that follows mutation in the MECP2 gene (chromosome Xq28). Previously recognized only in females, it is clear that males may survive and that the range of severity is wider than was originally appreciated, from mild learning disability to lethal neonatal encephalopathy. Anatomical, neurochemical and physiological studies indicate early failure of neuronal connectivity, specifically involving the brain stem and cerebral cortex, and provide fresh insight into normal and abnormal development. The emergence of a mouse model has improved the prospects for effective intervention.