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Clinical and biological progress over 50 years in Rett syndrome

Key Points

  • In the 50 years since its description by Andreas Rett, we have witnessed an explosion of knowledge about Rett syndrome (RTT) in relation to its genetic basis and clinical characteristics, and their interrelationships

  • Initially, the diagnosis of RTT was based solely on clinical criteria, but identification of its genetic cause has revolutionized this process, while presenting new challenges as we enter the era of next-generation sequencing

  • Mutations in the methyl-CpG-binding protein 2 (MECP2) gene were found to be causative of RTT, accounting for fundamentally altered neurobiological pathways, and providing the stimulus to identify pathways that can be manipulated therapeutically

  • The type of MECP2 mutation is associated with clinical severity, and influences many aspects of the phenotype, including functional abilities, onset of scoliosis, bone health, and sleep disturbances

  • Considerable progress has been made in understanding the natural history of RTT, leading to improvement in clinical management in selected areas, and changes in attitudes and allocation of health-care resources have increased life expectancy

  • The advancement in knowledge about RTT has been dependent on global efforts to study this disorder, including the establishment of database infrastructures, the input of advocacy groups, and the development of international collaborations

Abstract

In the 50 years since Andreas Rett first described the syndrome that came to bear his name, and is now known to be caused by a mutation in the methyl-CpG-binding protein 2 (MECP2) gene, a compelling blend of astute clinical observations and clinical and laboratory research has substantially enhanced our understanding of this rare disorder. Here, we document the contributions of the early pioneers in Rett syndrome (RTT) research, and describe the evolution of knowledge in terms of diagnostic criteria, clinical variation, and the interplay with other Rett-related disorders. We provide a synthesis of what is known about the neurobiology of MeCP2, considering the lessons learned from both cell and animal models, and how they might inform future clinical trials. With a focus on the core criteria, we examine the relationships between genotype and clinical severity. We review current knowledge about the many comorbidities that occur in RTT, and how genotype may modify their presentation. We also acknowledge the important drivers that are accelerating this research programme, including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we highlight the major milestones since 1966, and what they mean for the day-to-day lives of individuals with RTT and their families.

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Figure 1
Figure 2: The MECP2 gene and Rett syndrome.
Figure 3: Rett syndrome severity and age at diagnosis by mutation type.
Figure 4: Functional abilities and mutation type in Rett syndrome.
Figure 5: Comorbidities and mutation type in Rett syndrome.
Figure 6: Therapeutic strategies for Rett syndrome.

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Severe Rett syndrome phenotype. (MP4 27289 kb)

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Leonard, H., Cobb, S. & Downs, J. Clinical and biological progress over 50 years in Rett syndrome. Nat Rev Neurol 13, 37–51 (2017). https://doi.org/10.1038/nrneurol.2016.186

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