Rett Syndrome

Rett syndrome is an X-linked neurodevelopmental disorder affecting about 1 in 10,000 females, caused by loss-of-function variants in MECP2 (Xq28; over 95% of classic cases). More than 99% of cases are sporadic, with mutations occurring on the paternal X chromosome; other genes (CDKL5, FOXG1) cause variants with overlapping features that are now classified as separate disorders. Severe phenotypes occur in males with MECP2 variants (neonatal encephalopathy), while those with mosaicism or Klinefelter syndrome may have Rett like presentations.

Classic Rett syndrome has four stages:

• Stage I (6 to 18 months, early onset stagnation): slowing of head growth, hypotonia, reduced eye contact, and developmental plateau
• Stage II (1 to 4 years, rapid regression): loss of acquired purposeful hand skills and spoken language, stereotypic hand movements (wringing, washing, clapping, mouthing), social withdrawal, irritability, screaming episodes, sleep disturbance, and autistic features
• Stage III (pseudostationary, 2 to 10 years): partial recovery of social interaction and communication via eye gaze, but severe cognitive impairment, apraxia, ataxia, seizures (60 to 80%), breathing irregularities (hyperventilation, breath holding, air swallowing), bruxism, and scoliosis
• Stage IV (late motor deterioration, after 10 years): reduced mobility, rigidity, dystonia, scoliosis progression, muscle wasting and loss of ambulation

Other features: deceleration of head growth (acquired microcephaly), growth failure, cold blue feet, constipation, gastro oesophageal reflux, gallbladder disease, osteopenia, prolonged QT interval (about 20 to 30%), autonomic dysfunction, anxiety, and sudden unexpected death (cardiac arrhythmia, apnoea, seizure).

• The diagnosis is clinical, according to consensus criteria: required criteria are a period of regression followed by recovery or stabilisation, partial or complete loss of acquired purposeful hand skills, partial or complete loss of acquired spoken language, gait abnormalities (impaired or absent), and stereotypic hand movements. Exclusion criteria are brain injury, metabolic or neurological disease, and severe infection. Genetic testing (MECP2 sequencing and deletion or duplication analysis) confirms the diagnosis in over 95% of classic cases; if negative, test CDKL5 and FOXG1 or perform exome sequencing. Other investigations: EEG, ECG for QT interval, scoliosis radiographs, bone density, and swallow evaluation.

• Trofinetide (the first approved disease specific treatment; oral solution, weight based dosing 5 to 12 g twice daily for those 9 kg and above, a synthetic analogue of IGF-1 tripeptide) is licensed for patients aged 2 years and above; diarrhoea (about 80%) and vomiting are common, with dose adjustment and loperamide as needed.
• Seizures: valproate, lamotrigine, levetiracetam or carbamazepine, and ketogenic diet for refractory cases; avoid unnecessary medications, since many seizures are non-epileptic (behavioural events).
• Cardiac: baseline and periodic ECG; if QT is prolonged, avoid QT-prolonging drugs (macrolides, antipsychotics, some antiemetics, tricyclics) and consider beta blockers (propranolol, atenolol).
• Respiratory: manage hyperventilation and breath holding; buspirone and magnesium have been tried.
• Gastrointestinal: constipation (polyethylene glycol), reflux (omeprazole), gallstones (ultrasound if pain), and gastrostomy for failure to thrive (adequate calories are key for growth).
• Musculoskeletal: physiotherapy, bracing or spinal fusion for scoliosis above 40 to 50 degrees, hip surveillance, and orthoses; hydrotherapy.
• Bone: vitamin D (800 to 2000 IU/day), calcium, and weight bearing activities; bisphosphonates in fragility fractures.
• Communication: eye gaze technology and augmentative and alternative communication, which are key.
• Sleep: melatonin 2 to 10 mg at night and behavioural measures.
• Behaviour and mood: SSRIs for anxiety, and treatment of pain, constipation and reflux as the cause of distress.
• Palliative and supportive care, and family support. Survival into the fifth decade or longer is common.
• Genetic counselling: recurrence risk is low (about 1%) because of germline mosaicism, with prenatal testing offered.