Clinical and biological progress over 50 years in Rett syndrome

Abstract

It is fifty years since Andreas Rett first described Rett syndrome, a disorder now known to be caused by a mutation in the MECP2 gene. A compelling blend of astute clinical observations, clinical and laboratory research has already built our understanding of Rett syndrome and its biological underpinnings. We document the contributions of the early pioneers 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, the lessons from both cell and animal models and how they may inform future clinical trials. With a focus on the core criteria, we examine the relationships that have been demonstrated between genotype and clinical severity. We review what is known about the many comorbidities that occur in this disorder and how genotype may also modify their presentation. We acknowledge the important drivers that are accelerating this research program including the roles of research infrastructure, international collaboration and advocacy groups. Finally, we conclude by highlighting the major milestones since 1966 and what they mean for the day-to-day lives of those with Rett syndrome and their families. Key pointsThere has been an explosion of knowledge about Rett syndrome in relation to its genetic basis, clinical characteristics and their relationships during the fifty years since the disorder was first described by Andreas Rett.Whilst initially the diagnosis of Rett syndrome was based only on clinical criteria, identifying its genetic cause has had a major positive impact on how clinicians diagnose the disorder but also provides new challenges as we enter the era of next generation sequencing.

Novel and de novo mutations in pediatric refractory epilepsy

“…For example, most cases of Rett syndrome are now known to arise from mutations in the MECP2 gene, which codes for a methyl-CpG-binding protein 2 [90]. Another example is glucose transporter type 1 deficiency syndrome, which has been attributed to variants in SLC2A1, SLC2A2, and GLUT1.…”

Autonomic breathing abnormalities in Rett syndrome: caregiver perspectives in an international database study

“…Thus, in comparison, the onsets of breath-holding and hyperventilation, we identified, are occurring somewhat later, generally after the regression period. As with other clinical features [38], the age of regression also varies by genotype and is, for example, 10 months earlier in those with p.Arg106Trp than in those with C-terminal deletions [36]. Therefore, it is not possible to specify exactly the relationship between the stage of developmental regression as defined by Hagberg and Witt Engerstrom [39] 1986 and the onset of breathing irregularities.…”

Development of a Novel AAV Gene Therapy Cassette with Improved Safety Features and Efficacy in a Mouse Model of Rett Syndrome

“…Several mouse models of RTT have been generated that harbor Mecp2 deletions5, 6, 7 or knocked-in mutations 8, 9, 10, 11. Many of these models recapitulate the principal features that characterize RTT in humans, although there are differences that reflect the phenotypic variability seen in patients 12, 13, 14. Despite the severity of RTT-like phenotypes, genetic reactivation of silenced Mecp2 in conditional knockout mice resulted in a robust and enduring reversal of phenotypes 15, 16, 17…”