Conditions · Pediatrics and neonatology
Rett syndrome !
A genetic brain disorder, mostly in girls, where skills are lost after 6–18 months of normal growth, with hand-wringing and breathing problems.
Updated 2026-11-01
Structures involved
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Why it happens
- Mendelian inheritance: autosomal dominant, recessive and X-linked
- Epigenetics: DNA and histone methylation
- The neuron and synapse
What it is
An X-linked neurodevelopmental disorder, almost always due to MECP2 variants, that affects mainly girls. After an apparently normal first 6 to 18 months, the child loses purposeful hand use and spoken language and develops gait problems, stereotyped hand movements, breathing irregularities, deceleration of head growth and often seizures and scoliosis.
Who gets it
About 1 in 9,000 to 10,000 live-born girls; one of the most common genetic causes of severe intellectual disability in females. Over 95% of cases arise from a new (de novo) variant, usually on the paternal X chromosome. Affected boys are rare and usually have severe neonatal encephalopathy.
Causes
- Pathogenic variants in MECP2 (Xq28), which encodes methyl-CpG binding protein 2, in more than 95% of classic cases
- Variants in CDKL5 or FOXG1 cause related atypical forms
- Usually de novo; rarely inherited from a mother with favourable X inactivation
Risk factors
- Female sex (males with a MECP2 variant usually do not survive infancy or have a different, severe phenotype)
- Family history of a known MECP2 variant (rare)
Pathophysiology
MeCP2 regulates the expression of many neuronal genes and is essential for the maturation and maintenance of synapses. Loss of function leads to small, densely packed neurons with reduced dendritic branching, especially in the cortex, without neuronal death. Brain growth slows, causing acquired microcephaly. Brainstem and autonomic dysfunction explain breathing irregularities, and abnormal motor circuits cause dystonia, apraxia and scoliosis. Random X inactivation in girls explains the variable severity.
Classification
- Classic (typical) Rett syndrome: meets all main criteria
- Atypical (variant) forms: early-seizure (CDKL5), congenital (FOXG1) and preserved-speech variants
- Clinical stages: I early onset stagnation (6–18 months), II rapid regression (1–4 years), III pseudo-stationary, IV late motor deterioration
Symptoms and signs
- Normal or near-normal early development, then slowing and loss of acquired skills
- Loss of purposeful hand use, with stereotyped hand wringing, washing, clapping or mouthing
- Loss of spoken language and social withdrawal resembling autism, with later recovery of eye contact (eye pointing)
- Gait abnormalities: broad-based, apraxic gait or loss of walking
- Deceleration of head growth (acquired microcephaly)
- Breathing irregularities while awake: hyperventilation, breath-holding, air swallowing
- Seizures, sleep disturbance, bruxism, cold small hands and feet, constipation and poor growth
Diagnosis
- Clinical
- Clinical diagnosis based on a period of regression followed by recovery or stabilisation, plus all main criteria: partial or complete loss of purposeful hand skills, loss of spoken language, gait abnormalities and stereotypic hand movements. Head-circumference deceleration is supportive.
- Tests
- Genetic testing for MECP2 variants confirms most cases (a negative test does not exclude the clinical diagnosis); CDKL5 or FOXG1 if atypical. EEG for seizures; ECG to look for prolonged QT; nutritional and bone health assessment.
- Imaging
- Brain MRI is usually normal or shows non-specific reduced volume and is done to rule out other causes. Spine X-ray to follow scoliosis.
Differential diagnosis
- Autism spectrum disorder
- Angelman syndrome
- Cerebral palsy
- Neuronal ceroid lipofuscinoses and other neurodegenerative disorders
- Infantile spasms (West syndrome) and other epileptic encephalopathies
Goal of treatment
There is no cure; care is multidisciplinary and aims to maximise communication and mobility, control seizures and breathing problems, preserve nutrition and prevent orthopaedic and cardiac complications.
Treatment
- Medical
- Antiseizure medications for epilepsy; trofinetide is an approved disease-targeted medicine in some countries.
- Rehabilitation
- Physiotherapy and hydrotherapy to maintain walking, balance and posture; splints for hand stereotypies.
- Rehabilitation
- Occupational and speech therapy with augmentative communication (eye-gaze devices, picture boards).
- Medical
- Medical management of reflux, constipation, sleep problems and agitation; avoid drugs that prolong the QT interval.
- Conservative
- Nutritional support (high-calorie diet, gastrostomy if swallowing is unsafe) and bone health care.
- Follow-up
- Monitoring: regular ECG, growth, spine (scoliosis bracing or surgery) and family support.
Complications
- Scoliosis requiring bracing or spinal surgery
- Epilepsy
- Malnutrition, dysphagia and aspiration pneumonia
- Prolonged QT interval and sudden unexpected death
- Osteopenia and fractures
- Gastro-oesophageal reflux, constipation and gallbladder disease
Prognosis
Most girls survive into adulthood, many into middle age, with severe lifelong disability. Regression stabilises after early childhood, and some communication and eye contact improve, but motor function often declines later in life.
Test yourself
Think of the answer, then tap the question to see it.
What gene is mutated in most cases of Rett syndrome?
MECP2 on the X chromosome (Xq28), usually a de novo variant.
What is the classic hand finding?
Loss of purposeful hand use with stereotyped midline hand wringing or washing movements.
What is the typical timeline?
Apparently normal development for 6 to 18 months, then regression of language and motor skills.
Why is it seen almost only in girls?
It is X-linked; most affected males do not survive or have severe neonatal encephalopathy, while mosaic X inactivation lets girls survive.
Which cardiac test should be done regularly?
ECG, because prolonged QT may cause sudden death.
Related conditions
- Autism spectrum disorder (ASD)
- Epilepsy and seizures
- Cerebral palsy
- Prader–Willi and Angelman syndromes (imprinting)
- Scoliosis
- Infantile spasms (West syndrome)
Educational information, not medical advice. For any symptom, see a health professional.
Sources: Rett syndrome (MedlinePlus Genetics (U.S. National Library of Medicine), 2024).
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