Rett Syndrome

Rett syndrome is a rare and complex neurological disorder that predominantly affects females and typically becomes apparent after a period of normal development during infancy (1). First described by Austrian physician Dr. Andreas Rett in 1966, the syndrome is characterized by a gradual loss of motor and communication skills. Rett syndrome is classified as a neurodevelopmental disorder and is considered one of the most common causes of intellectual disability in females. Though it shares some symptoms with autism spectrum disorders, Rett syndrome is distinct in its progression and genetic origins.

This condition affects approximately 1 in every 10,000 to 15,000 live female births globally (1). Males with the mutation rarely survive infancy, as the disorder is linked to the X chromosome, making females the predominant affected population. While Rett syndrome currently has no cure, early intervention and supportive treatments can significantly improve quality of life.

Symptoms

Rett syndrome presents in stages, with symptoms emerging after a period of seemingly typical development. The main symptoms include:

• Loss of purposeful hand skills such as grasping or manipulating objects (3).
• Development of repetitive hand movements, like wringing, tapping, or clapping (3).
• Slowed growth, especially in head circumference (microcephaly).
• Speech regression, where previously acquired words and communication abilities diminish.
• Motor abnormalities, such as difficulty walking, uncoordinated movements, and poor muscle tone.
• Breathing irregularities, including hyperventilation, breath-holding, and apnea, especially during wakefulness.
• Seizures, which may become more frequent as the condition progresses.
• Social withdrawal, though in many cases, eye contact and emotional connection remain strong.
• Sleep disturbances, with frequent night waking and irregular sleep patterns.

These symptoms usually start to appear between 6 months to 18 months of age and progress through several defined stages, each with varying intensities and manifestations.

Causes

Rett syndrome is primarily caused by mutations in the MECP2 gene, located on the X chromosome (2). The MECP2 gene produces a protein essential for brain development and the regulation of other genes. Most cases result from spontaneous mutations rather than inherited changes, meaning that there is typically no family history of the disorder.

This mutation disrupts normal synaptic development and neuronal communication in the brain, leading to the array of physical, cognitive, and behavioral symptoms characteristic of Rett syndrome (2). While hundreds of different MECP2 mutations have been identified, the severity of the disorder often depends on the specific nature and location of the mutation.

Risk Factors

Although Rett syndrome is primarily a genetic disorder, certain factors may influence the likelihood or severity of its development:

• Gender: Since the mutation affects the X chromosome, females are far more likely to survive and manifest symptoms, while males with the mutation often experience fatal complications early in life.
• Spontaneous mutation: Most cases occur sporadically, with no known risk factors or triggers in family history.
• Parental age: While the mutation is typically random, some research suggests that advanced paternal age may slightly increase the risk of new gene mutations, including those causing Rett syndrome.

Having a child with Rett syndrome is not usually associated with any lifestyle or environmental choices made during pregnancy (3).

Diagnosis

Diagnosing Rett syndrome involves a combination of clinical observation and genetic testing. Key diagnostic steps include (3):

1. Developmental history review: Pediatricians evaluate the child’s developmental milestones and identify any signs of regression.
2. Physical and neurological examination: To observe hand movements, coordination, speech ability, and other symptoms.
3. Genetic testing: Confirmation is typically achieved through identifying a mutation in the MECP2 gene using blood tests.
4. Differential diagnosis: Rett syndrome must be distinguished from other neurodevelopmental conditions like autism spectrum disorder, cerebral palsy, or metabolic disorders (2).

Because Rett syndrome shares overlapping symptoms with other conditions, particularly in early stages, accurate diagnosis may take time and specialized expertise.

Treatment Options

There is currently no cure for Rett syndrome. However, a combination of therapies and interventions can help manage symptoms and enhance the patient’s quality of life. Treatment is usually multidisciplinary and includes (3):

• Medication: To control seizures, breathing irregularities, and mood disorders such as anxiety or agitation.
• Physical therapy: Improves mobility, balance, and muscle tone.
• Occupational therapy: Focuses on enhancing hand function and daily living skills.
• Speech therapy: Though verbal communication may be limited, therapists can help patients utilize alternative communication methods like eye-gaze devices or sign language.
• Nutritional support: Children with Rett syndrome often experience feeding difficulties, requiring specialized diets or feeding tubes.
• Behavioral therapy: Helps with mood regulation and social interaction.

Emerging therapies, including gene therapy, MECP2 reactivation, and targeted molecular treatments, are currently under investigation in clinical trials and hold promise for future treatment avenues (3).

Living With or Prevention

Living With Rett Syndrome

Living with Rett syndrome presents numerous challenges, not just for the affected individual but also for their families. However, with appropriate care and support, many individuals live into adulthood and can experience a meaningful quality of life. Families often work closely with neurologists, therapists, and educational specialists to develop personalized care plans (3).

Support groups, special education programs, and advocacy organizations also play a crucial role in helping families navigate the emotional, physical, and financial aspects of caring for a child with Rett syndrome (3).

Key strategies for improving life quality include:

• Creating a structured daily routine.
• Adapting the home environment for safety and accessibility.
• Using communication aids to facilitate interaction.
• Ensuring regular medical monitoring and therapy sessions.

Prevention

Because Rett syndrome typically arises from spontaneous genetic mutations, there is currently no known method of prevention. However, in families with a history of MECP2-related disorders, genetic counseling can provide insight into reproductive risks and help inform future planning (3).

References

1. Bienvenu T, Philippe C, De Roux N, Raynaud M, Bonnefond JP, Pasquier L, Lesca G, Mancini J, Jonveaux P, Moncla A, Feingold J, Chelly J, Villard L. The incidence of Rett syndrome in France. Pediatr Neurol. 2006 May;34(5):372-5. doi: 10.1016/j.pediatrneurol.2005.10.013. PMID: 16647997.
2. Brunetti S, Lumsden DE. Rett Syndrome as a movement and motor disorder – A narrative review. Eur J Paediatr Neurol. 2020 Sep;28:29-37. doi: 10.1016/j.ejpn.2020.06.020. Epub 2020 Jul 28. PMID: 32807681.
3. Asuncion RMD, Ramani PK. Rett Syndrome. [Updated 2025 Mar 27]. In: StatPearls [Internet]. Treasure Island (FL): StatPearls Publishing; 2025 Jan-. Available from: https://www.ncbi.nlm.nih.gov/books/NBK482252/