Rett syndrome

Rett syndrome is a severe neurodevelopmental disorder that primarily affects the central nervous system. It is caused by pathogenic variants in the MECP2 gene, and most affected individuals are female due to the X‐linked dominant inheritance pattern. The condition typically presents with a period of seemingly typical early development, followed by profound developmental regression. Birth prevalence estimates indicate that it affects approximately 1 in 10,000 to 15,000 female births, and overall it is considered an uncommon condition.

After a period of apparently typical early development, affected children experience a phase of developmental regression marked by loss of previously acquired skills, including deterioration in motor function and cognitive abilities. Characteristic clinical features include loss of purposeful hand use accompanied by stereotypical hand wringing behaviors, intermittent hyperventilation, and seizures that occur in all affected individuals. In addition to these core symptoms, patients may also exhibit gait abnormalities such as ataxia and challenges with spoken language. Not all individuals experience all features, and severity varies considerably.

Rett syndrome is predominantly caused by pathogenic variants in the MECP2 gene, which plays a critical role in regulating gene expression in the brain. Most cases arise from de novo mutations, meaning the genetic change is not inherited from either parent, although in rare instances germline mosaicism can increase recurrence risk for subsequent pregnancies. This condition follows an X‐linked dominant inheritance pattern, with affected females typically exhibiting the syndrome while males are more severely affected or may not be viable. Genetic counseling is recommended to help families understand the implications of the genetic findings and for guidance on family planning.

Currently, management focuses on supportive care and symptom management, as there are no treatments specifically approved for Rett syndrome. Foundational therapies include seizure management with antiepileptic medications, physical therapy to maintain mobility and prevent contractures, speech therapy with augmentative and alternative communication strategies, occupational therapy to improve hand function and daily living skills, and nutritional as well as feeding support. A multidisciplinary team that may include neurologists, developmental pediatricians, geneticists, genetic counselors, physical therapists, speech-language pathologists, and pulmonologists is typically involved. Patients and their families are encouraged to discuss treatment options with their care team and consider genetic counseling for further guidance.

Rett syndrome is a lifelong neurodevelopmental condition characterized by an initial regression followed by a period of relative stabilization and, in some individuals, later motor decline. Outcomes vary widely between individuals, and while some may experience stabilization after the regression phase, others may encounter additional challenges as they age. With current standards of care, many individuals live into adulthood, and advances in supportive care have meaningfully improved quality of life over the years. Outcomes described in medical literature continue to evolve as standards of care improve. Families often find it helpful to connect with specialists familiar with the condition and to seek genetic counseling for ongoing support and guidance.

Rett syndrome remains an active research area with numerous ongoing clinical trials investigating new treatment approaches. Key research directions include gene therapy strategies, MECP2 reactivation methods, and targeted therapies such as trofinetide, which may lead to modest improvements in some neurological symptoms in certain individuals, though responses vary. Individuals interested in clinical trials can search ClinicalTrials.gov or consult their care team about eligibility.