Rett syndrome – advances in gene and trofinetide therapy

Abstract

Rett syndrome is a rare, severe neurodevelopmental disorder with X-linked dominant inheritance. It mainly affects women, causing cognitive and physical impairments due to rapid developmental regression in infancy. Rett syndrome is usually recognised in children between six and 18 months old, when they begin to miss developmental milestones or lose the abilities they have gained. One characteristic symptom involves continuous repetitive hand movements. Rett syndrome is one of the most common causes of complex disability in girls. However, the condition can be misdiagnosed. Differential diagnoses that should be considered include cerebral palsy, autism, Angelman syndrome, and non-specific developmental delay. Rett syndrome is related to the loss-of-function mutations in the gene encoding methyl-CpG-binding protein 2 (approximately 90% of reported cases). These mutations have been associated with impacting the development of neurons and axodendritic connections. Progress has been made over the past 50 years since the first report of Rett syndrome. Several promising clinical trials and exciting novel therapeutic options are being tested in both laboratory and clinical settings. Research findings led to the registration in March 2023 of the first drug for therapy, trofinetide. The medication was found to improve brain function and communication skills in recent studies. There are also promising clinical trials investigating the replacement of the mutated gene. This study aims to analyse the latest pharmacological treatment and gene therapy in Rett syndrome, which brings a glimmer of hope to patients and their families, who anticipate a future where Rett syndrome is a reversible and curable condition.