Rett Syndrome
Rett syndrome is a rare, X-linked neurodevelopmental disorder affecting approximately 1 in 10,000 to 22,000 female live births. It is caused by a spontaneous pathogenic variant in the MECP2 gene, located on the X chromosome. This gene is crucial for the function of the MeCP2 protein, which regulates gene expression and is essential for normal brain development.
Over 99% of cases are de novo mutations, meaning they are not inherited from the parents.
In females, the presence of two X chromosomes and the process of random X-inactivation can lead to a mosaic expression of the mutated gene. This accounts for the wide variability in symptom severity.
While far less common, Rett syndrome can occur in males, often leading to a more severe phenotype, as they lack a second X chromosome to compensate for the mutation.
Clinical Presentation and Diagnostic Criteria
The clinical course of Rett syndrome is typically divided into four stages, though there can be significant overlap.
Stage 1: Early Onset (6-18 months): Often overlooked, with subtle signs such as decreased eye contact, disinterest in toys, and delays in gross motor skills (sitting, crawling).
Stage 2: Rapid Deterioration/Regression (1-4 years): The hallmark of the syndrome. A rapid or gradual loss of previously acquired purposeful hand skills and spoken language. This is accompanied by the onset of characteristic hand stereotypies (wringing, squeezing, clapping, mouthing), gait abnormalities, and social withdrawal.
Stage 3: Plateau (2-10 years): A period of stability and possible improvement. Irritability may lessen, and there can be an increase in social engagement, alertness, and non-verbal communication. However, motor problems and seizures often remain prominent.
Stage 4: Late Motor Deterioration (after age 10): Characterised by reduced mobility, muscle rigidity, and the development or worsening of scoliosis. Cognitive and communication skills typically remain stable during this phase, and seizures may become less frequent.
Diagnosis is clinical, based on a set of criteria from a paediatric neurologist or geneticist, and is confirmed by genetic testing for a pathogenic MECP2 variant.
Management and Recent Developments
Management of Rett syndrome in the UK is multidisciplinary and symptom-focused, aiming to improve quality of life.
Therapies: A robust regimen of physical therapy, occupational therapy, and speech and language therapy is crucial. These help with mobility, posture, and communication.
Symptomatic Management: Medications are used to control seizures, manage gastrointestinal issues (e.g., constipation, reflux), and address sleep disturbances.
Recent Therapeutic Developments: The last few years have seen a surge in research, particularly in gene therapy. Clinical trials for treatments that aim to deliver a working copy of the MECP2 gene are underway, with the first UK gene therapy trial site now open at the Royal Manchester Children’s Hospital. While this is an international trial and is currently in its early stages, it represents a significant step forward, offering a potential disease-modifying therapy rather than just symptomatic relief.
For family and professional support, Rett UK and the Rett Registry UK are key resources. The registry, in particular, is vital for demonstrating the need for new therapies and for recruiting patients for future clinical trials.