Rett Syndrome

Rett Syndrome (RS) is a monogenic, X-linked dominant neurodevelopmental disorder that primarily affects girls. After an initially normal developmental course during the first months of life, it typically progresses with a gradual and characteristic regression. In most cases, it is associated with mutations in the MECP2 (methyl-CpG binding protein 2) gene on the X chromosome. The MECP2 protein plays a role in regulating gene expression in neurons, and its mutation directly impacts neuronal development.

^{A visual representing Rett Syndrome. (Generated by artificial intelligence.)}

Rett Syndrome typically presents in girls who have shown normal development during the first six months after birth, with a period of stagnation beginning around six months of age, followed by loss of acquired skills. The disorder generally progresses through four stages:

1. Stagnation stage (6–18 months): Slowing of motor and social interactions.
2. Rapid regression stage (1–4 years): Dramatic loss of speech, purposeful hand skills, and motor abilities; autism-like features.
3. Pseudo-stabilization stage: Hand stereotypies (e.g. hand washing, wringing), eye gaze communication, and epilepsy.
4. Late motor deterioration stage: Inability to walk, spasticity, scoliosis, dystonia, muscle atrophy, and joint contractures.

The main clinical findings of Rett Syndrome include:

• Partial or complete loss of purposeful hand skills
• Loss of speech and communication impairments
• Hand stereotypies (hand clapping, wringing, mouthing, etc.)
• Gait abnormalities, ataxia, and apraxia
• Microcephaly (stagnation and reduction in head circumference)
• Epileptic seizures
• Respiratory irregularities (hyperventilation, breath holding)
• Frequently cold, bluish hands and feet
• Sleep disturbances and nocturnal screaming
• Eye gaze communication behavior (eye-pointing)
• Increased muscle tone, scoliosis, and foot deformities

Rett Syndrome occurs in approximately one in every 10,000 to 20,000 live female births worldwide. In males, MECP2 mutations typically result in intrauterine or early postnatal death, making the condition rarely detected. Consequently, the syndrome is almost exclusively diagnosed in girls. Some males may survive with mild symptoms, but this is usually associated with mosaic mutations or X-chromosome abnormalities.