From the Guidelines
Rett syndrome is a rare genetic neurological disorder that primarily affects girls and is characterized by normal early development followed by a regression of skills, particularly affecting language, motor abilities, and purposeful hand movements. It is caused by mutations in the MECP2 gene on the X chromosome, which produces a protein important for brain development 1. Symptoms typically appear between 6-18 months of age and include loss of speech and motor skills, repetitive hand movements (hand wringing, clapping, or washing movements), breathing irregularities, sleep problems, seizures, growth delays, and intellectual disability. There is no cure for Rett syndrome, but treatment focuses on managing symptoms through medications for seizures (such as valproic acid, carbamazepine, or levetiracetam), physical therapy to maintain mobility, occupational therapy for daily living skills, speech therapy, and nutritional support 1. Some patients may benefit from medications to address specific symptoms like breathing irregularities or sleep disturbances. Despite significant disabilities, many individuals with Rett syndrome live into adulthood with appropriate supportive care. Research continues to explore potential gene therapies and other treatments that might address the underlying genetic cause, with recent studies suggesting that MECP2 mutations are a primary etiology of Rett syndrome and that testing for these mutations may be beneficial in certain cases 1. Key considerations in the management of Rett syndrome include:
- Early diagnosis and intervention to improve outcomes
- Multidisciplinary care, including physical, occupational, and speech therapy
- Management of symptoms, such as seizures and breathing irregularities
- Nutritional support and monitoring of growth and development
- Ongoing research into potential gene therapies and other treatments.
From the Research
Definition and Characteristics of Rett Syndrome
- Rett syndrome (RTT) is a unique neurodevelopmental disorder that primarily affects females, resulting in severe cognitive and physical disabilities 2, 3.
- It is characterized by developmental regression of spoken language and hand use, hand stereotypies, and impaired ambulation, which constitute the four core diagnostic features 4.
- RTT is a severe, progressive disorder that affects predominantly females, with a global prevalence of 5 to 10 cases per 100,000 females 5.
Genetic Etiology
- RTT is mainly caused by pathogenic variants in the MECP2 gene, which regulates gene expression and is highly expressed in the brain 4, 5, 6.
- The MECP2 gene is involved in epigenetic gene regulation, neurotransmitter action, and RNA transcription/translation 3.
- Other genes associated with RTT and Rett-like phenotypes have been identified, highlighting the clinical and genetic heterogeneity of the Rett syndrome spectrum 3.
Clinical Features and Comorbidities
- Individuals with RTT may present with multiple neurological impairments and comorbidities, such as seizures, breathing irregularities, anxiety, and constipation 4.
- RTT affects not only neurological function but also a wide array of non-neurological organs, including the respiratory, cardiovascular, digestive, metabolic, skeletal, endocrine, muscular, and urinary systems, as well as the immune response 6.
- The disorder is associated with reductions in brain size and global decreases in neuronal size, as well as alterations in multiple neurotransmitter systems 4.
Management and Treatment
- Management of RTT is mainly focused on preventing the progression of symptoms, currently improved by guidelines based on natural history studies 4.
- Trofinetide, an IGF1-related compound, is an approved drug for RTT, which has shown favorable safety and efficacy profiles by improving several core RTT symptoms 5.
- Other drugs and gene therapies are currently under investigation, offering promising treatment options for individuals with RTT 4, 5.