Rett Syndrome: From Recognition to Diagnosis to Intervention

Alan K Percy


Expert Rev Endocrinol Metab. 2008;3(3):327-336. 

In This Article

Abstract and Introduction

Rett syndrome is a relatively rare neurodevelopmental disorder (incidence: approximately one out of 10,000 female births) that reached worldwide prominence in the early 1980s. Owing to its overwhelming predominance in females, Rett syndrome was regarded as a genetic disorder. However, its occurrence is sporadic, with a recurrence risk well below 0.5%. In 1999, confirmation was provided by the demonstration of mutations in the MECP2 gene. At present, more than 95% of females who fulfill consensus criteria for Rett syndrome have a mutation in this gene. Over the past 25 years, understanding of the clinical features and natural history of this unique neurodevelopmental disorder has evolved dramatically. However, large segments of healthcare professionals and the general public still remain relatively uninformed. This review details the clinical picture of Rett syndrome and the diagnostic strategies required, explores the critical medical issues and recent advances in molecular neurobiology, provides an overview of intervention strategies that have been developed to date and sets the stage for future treatment trials as novel, and potentially effective, pharmacologic or molecular interventions become available.

Physicians and related healthcare professionals, basic scientists and educators are, generally, uninformed about Rett syndrome (RS). Indeed, RS is a relative newcomer to the field of neurodevelopmental disorders. Despite being one of the 'new kids on the block', significant advances have emerged in recent years regarding our understanding of the clinical features, molecular genetics and neurobiology of RS, particularly following the recognition that mutations in the gene, MECP2, are responsible. In the absence of a fundamental therapy, serious energies have been directed to developing rational intervention strategies. Excitement was generated within the past year by the potential for reversing the devastating consequences of RS.[1,2] Through molecular manipulation, a mouse model for RS was engineered to allow activation of Mecp2 once the mice had developed the clinical phenotype associated with absence of this gene. At the same time, studies in another mouse model provided important new information on the molecular neurobiology of RS.[3,4] These studies allowed the authors to suggest a neuroendocrine component involving elevated corticotrophinreleasing hormone (Crh) and elevated corticosterone levels (cortisol in humans) in the pathobiology of this disorder. Taken together, the findings support the notion that the clinical features of RS could be modified by appropriate interventions and suggest at least one potential avenue for doing so. This review provides background information on RS, including diagnosis, medical issues, genetics and molecular neurobiology, and explores potential therapeutic strategies.


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