Rett syndrome affects approximately 1 in 10,000 to 15,000 females worldwide and has been reported across all racial and ethnic groups. It is considered a rare disorder, with an estimated incidence of 1 in 10,000 female births. The condition is much rarer in males, as most affected males do not survive to birth or early infancy due to the lack of a second X chromosome to compensate. When it does occur in males, it is typically due to specific mutations or genetic variations that allow for survival, or in individuals with more than one X chromosome (such as XXY; see RareShare Guide on Genetic Inheritance). With advances in genetic testing, the condition is now more readily recognized, especially in children who show regression after an initial period of normal development.

Rett syndrome is primarily caused by mutations in the MECP2 gene, located on the X chromosome. This gene provides instructions for making a protein called methyl-CpG-binding protein 2, which is critical for normal brain development and functioning. The MECP2 protein regulates gene expression by turning other genes on or off at specific times during development. When this protein is defective or absent, it affects the function of many other genes involved in brain development and maintenance.

Most cases of Rett syndrome (approximately 95%) are caused by de novo mutations, meaning the mutation occurs spontaneously and is not inherited from parents. A small percentage of cases may be inherited from mothers who carry the mutation but do not show symptoms due to favorable X chromosome inactivation patterns. People with mutations in CDKL5 and FOXG1 genes (both important for early brain development) share some features with people with Rett syndrome. However, newer research suggests that there are enough important differences in the underlying biology and symptom progression to consider them distinct disorders rather than variants of RTT.

Symptoms of RTT appear in stages and vary in severity, but hallmark features include:

• Early Development Followed by Regression: Normal growth and development for 6–18 months, followed by a rapid decline in motor skills and communication abilities.

• Loss of Purposeful Hand Skills: Replaced by repetitive, stereotyped movements such as hand-wringing, clapping, or mouthing.

• Communication Difficulties: Loss of spoken language and social engagement, often misinterpreted as autism in early stages.

• Motor Impairments: Loss of coordination, balance issues, abnormal gait, and muscle tone abnormalities.

• Seizures: Occur in 50–90% of individuals, often beginning in early childhood.

• Breathing Abnormalities: Episodes of hyperventilation, breath-holding, and irregular breathing patterns, especially while awake.

• Other Symptoms: Scoliosis, slowed growth, microcephaly (small head size), sleep disturbances, digestive problems, and bruxism (teeth grinding).

Diagnosis of Rett syndrome is based on clinical symptoms and genetic testing.

Diagnostic Tests:

• Genetic Testing: Sequencing of the MECP2 gene, which confirms approximately 95% of typical Rett syndrome cases. 

• Electroencephalogram (EEG): To evaluate seizure activity 

• Brain MRI: To rule out other neurological conditions

• Developmental Assessments: Speech, motor, and cognitive evaluations help guide intervention plans.

There is currently no cure for RTT, but treatment is supportive and focuses on managing symptoms, maximizing functional abilities, and improving quality of life through a multidisciplinary care approach:

• Therapies: Physical, occupational, and speech therapy are critical for preserving mobility, promoting communication, and enhancing daily function.

• Seizure Management: Antiepileptic drugs are prescribed based on seizure type and severity.

• Behavioral and Educational Support: Special education services and individualized programs tailored to cognitive and behavioral needs.

• Nutritional Support: High-calorie diets, feeding support, and management of gastrointestinal issues are often necessary.

• Assistive Technology: Communication devices and mobility aids may support independence and engagement.

• Surgical Interventions: May be needed for severe scoliosis or other orthopedic complications.

The prognosis for individuals with Rett syndrome varies significantly. While it is a lifelong condition with no cure, many individuals with Rett syndrome live into adulthood with appropriate care and support. Life expectancy has improved significantly with better understanding and management of the condition, with many individuals now living into their 40s and 50s.

Key prognostic factors include:

• Type and location of the MECP2 mutation

• Severity of symptoms

• Quality of supportive care

• Management of associated conditions (seizures, scoliosis, etc.)

• Early intervention and consistent therapy

While motor skills typically plateau or deteriorate over time, cognitive abilities may remain stable after the initial regression phase. Many individuals with Rett syndrome develop meaningful ways to communicate through assistive technologies, allowing for improved quality of life despite significant physical limitations.

For more information, please visit the International Rett Syndrome Foundation: https://www.rettsyndrome.org/about-rett-syndrome/understanding-rett-syndrome/

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