Rett syndrome is a neurodevelopmental disorder most often caused by pathogenic variants in MECP2. Epilepsy affects many, but not all, people with Rett syndrome, and several characteristic non-epileptic behaviours can closely resemble seizures.
Classic Rett syndrome
Classic Rett syndrome usually affects girls who have apparently typical early development followed by developmental stagnation and then regression, especially in purposeful hand use and spoken language.
Hand stereotypies, gait abnormalities, breathing irregularities and acquired microcephaly are common.
MECP2
MECP2 encodes methyl-CpG-binding protein 2, an important regulator of gene expression in the nervous system.
Most classic cases arise from a de novo pathogenic variant.
Epilepsy frequency
Current GeneReviews data estimate seizures in approximately 60–80% of females with classic Rett syndrome.
Frequency and severity vary by phenotype and genotype.
Age at seizure onset
Epilepsy often appears after the period of early developmental regression rather than in the neonatal period.
Very early severe epilepsy should raise consideration of other disorders such as CDKL5 deficiency disorder.
Seizure types
Focal, tonic-clonic, myoclonic, tonic and other seizure types can occur.
No single seizure type defines Rett syndrome.
Non-epileptic events that mimic seizures
Breath-holding, hyperventilation, staring, hand stereotypies, dystonia, tremor and other movement events can resemble epileptic seizures.
Studies have shown that many apparent “vacant spells” in Rett syndrome are non-epileptic.
Why video-EEG matters
When frequent unusual events are being considered for treatment escalation, video-EEG can help determine whether they are epileptic.
This can prevent unnecessary polypharmacy.
EEG
EEG often becomes increasingly abnormal with age, even in people without frequent clinical seizures.
Abnormal EEG alone should therefore not be treated as proof that every observed behaviour is epileptic.
Treatment
There is no universally superior antiseizure medicine for Rett syndrome.
Treatment is selected according to seizure type, response, adverse effects and coexisting medical problems.
Drug resistance
A subset develop drug-resistant epilepsy.
Earlier seizure onset and very frequent seizures have been associated with poorer seizure-control outcomes in observational cohorts.
Breathing abnormalities
Breath-holding, hyperventilation and apnoea-like episodes are part of the Rett phenotype and are often not epileptic.
Careful event characterisation is important because respiratory events can be frightening and easily mislabelled as seizures.
Cardiac considerations
Rett syndrome can be associated with QT-interval abnormalities and autonomic dysfunction.
Medication choices should therefore consider cardiac risk and drug interactions.
Movement and orthopaedic care
Dystonia, spasticity, scoliosis and mobility limitations can become major clinical issues.
Management requires multidisciplinary care beyond epilepsy treatment.
CDKL5 and FOXG1 are distinct disorders
CDKL5 deficiency disorder and FOXG1 syndrome were historically described as Rett variants.
They are now recognised as distinct genetic disorders with different natural histories and epilepsy patterns.
Males with MECP2 disorders
Males can have severe neonatal encephalopathy, intellectual disability or other MECP2-related phenotypes.
The clinical spectrum differs from classic female Rett syndrome.
Genetic counselling
Most cases are de novo, but parental germline mosaicism and rare inherited variants can occur.
Molecular confirmation is important for recurrence-risk counselling.
Worldwide access
Diagnosis requires clinical recognition and molecular testing.
Access to Rett-specific multidisciplinary care, respiratory assessment, communication technology and specialist epilepsy services remains unequal.
The central point
Not every unusual event in Rett syndrome is a seizure. Accurate distinction between epilepsy, breathing behaviours and movement abnormalities is essential to avoid both undertreatment and overtreatment.
Related reading
CDKL5 Deficiency Disorder and Epilepsy →
Genetic Testing in Epilepsy →
Sources
- GeneReviews — MECP2 Disorders, updated 2025
- Epilepsy in Rett syndrome — phenotype, genotype and implications for practice
Medical note: repeated staring, breathing or movement events in Rett syndrome may be epileptic or non-epileptic; video-EEG is often valuable when the distinction changes treatment.
Evidence checked: September 2026.