Rett Syndrome

Overview

Plain-Language Overview

Rett Syndrome is a rare genetic disorder that primarily affects girls and leads to severe developmental problems. Children with this condition often develop normally for the first 6 to 18 months but then lose previously acquired skills such as speech and purposeful hand use. They may develop repetitive hand movements like wringing or clapping. Other common features include problems with walking, seizures, and difficulties with breathing. Rett Syndrome is caused by mutations in a gene important for brain development and function.

Clinical Definition

Rett Syndrome is a neurodevelopmental disorder caused by mutations in the MECP2 gene located on the X chromosome. It predominantly affects females due to its X-linked dominant inheritance pattern, with males rarely surviving infancy. The disorder is characterized by a period of apparently normal early development followed by a regression phase during which there is loss of purposeful hand skills and spoken language. Patients develop distinctive repetitive hand movements such as hand wringing or washing motions. Other clinical features include gait abnormalities, seizures, microcephaly, and autonomic dysfunction such as irregular breathing patterns. Cognitive impairment is profound, and affected individuals often have severe motor disabilities. Brain imaging may show nonspecific atrophy, but diagnosis is primarily clinical supported by genetic testing. The syndrome progresses through stages including early onset stagnation, rapid regression, plateau, and late motor deterioration. Management is supportive and multidisciplinary, focusing on symptom control and improving quality of life.

Inciting Event

The inciting event is a spontaneous mutation in the MECP2 gene during early embryonic development.

Latency Period

Symptoms typically begin after a period of apparently normal development lasting 6 to 18 months.

Diagnostic Delay

Early symptoms can be subtle and nonspecific, leading to delayed recognition of developmental regression.
Misdiagnosis as autism spectrum disorder or cerebral palsy can contribute to diagnostic delay.

Clinical Presentation

Signs & Symptoms

Normal early development followed by regression of acquired skills between 6-18 months.
Loss of purposeful hand use with development of repetitive hand-wringing movements.
Severe cognitive impairment and developmental delay.
Seizures are common and may be difficult to control.
Breathing irregularities including hyperventilation and apnea episodes.
Autistic features such as social withdrawal and impaired communication.

History of Present Illness

Initial normal development followed by loss of acquired speech and purposeful hand skills between 6 and 18 months of age.
Development of characteristic hand-wringing or hand-washing stereotypies.
Onset of gait abnormalities, including ataxia and apraxia.
Progressive microcephaly and deceleration of head growth.
Seizures, breathing irregularities, and autistic features may develop later.

Past Medical History

Typically unremarkable early infancy with normal growth and development prior to symptom onset.

Family History

Most cases are sporadic with no family history due to de novo mutations in MECP2.
Rare familial cases may show X-linked dominant inheritance with variable expression in female relatives.

Physical Exam Findings

Patients often exhibit microcephaly with deceleration of head growth.
There is typically loss of purposeful hand skills with development of stereotypic hand movements such as hand-wringing.
Examination reveals gait abnormalities including ataxia and apraxia.
Muscle tone abnormalities such as hypotonia or later spasticity are common.
Patients may show diminished or absent deep tendon reflexes.

Diagnostic Workup

Diagnostic Criteria

The diagnosis of Rett Syndrome requires a period of apparently normal early development followed by a clear regression of hand skills and spoken language. Core criteria include the development of repetitive hand movements such as hand wringing, loss of purposeful hand use, and impaired gait or inability to walk. Additional features supporting diagnosis include slowed head growth resulting in microcephaly, seizures, and breathing irregularities. Genetic testing confirming a pathogenic mutation in the MECP2 gene supports the diagnosis but is not solely diagnostic. The clinical presentation must exclude other neurological or metabolic disorders that could explain the symptoms.

Pathophysiology

Key Mechanisms

Rett syndrome is caused by mutations in the MECP2 gene, which encodes methyl-CpG-binding protein 2, a critical regulator of neuronal gene expression.
Loss of functional MECP2 protein leads to impaired synaptic development and neuronal maturation, resulting in neurodevelopmental regression.
Dysfunction in glial cells and altered neurotransmitter systems contribute to the neurological symptoms.

Involvement	Details
Organs	Brain is the primary organ affected, with progressive neurodevelopmental regression.
Organs	Heart may be involved due to autonomic dysfunction causing arrhythmias.
Tissues	Cortical gray matter shows reduced volume and abnormal neuronal morphology in Rett syndrome.
Tissues	White matter abnormalities reflect disrupted myelination and connectivity.
Cells	Neurons are primarily affected in Rett syndrome, leading to impaired brain function.
Cells	Glial cells contribute to neuroinflammation and support neuronal health in the CNS.
Chemical Mediators	Brain-derived neurotrophic factor (BDNF) is decreased, impairing neuronal survival and synaptic plasticity.
Chemical Mediators	Glutamate dysregulation contributes to excitotoxicity and neuronal damage.

Treatment

Pharmacological Treatments

Antiepileptic drugs
- Mechanism: Control seizures by modulating neuronal excitability
- Side effects: drowsiness, dizziness, gastrointestinal upset
Selective serotonin reuptake inhibitors (SSRIs)
- Mechanism: Improve mood and reduce anxiety by increasing serotonin levels
- Side effects: nausea, headache, sexual dysfunction
Baclofen
- Mechanism: Acts as a GABA_B receptor agonist to reduce spasticity
- Side effects: muscle weakness, fatigue, dizziness

Non-pharmacological Treatments

Physical therapy helps maintain mobility and reduce contractures.
Speech therapy supports communication skills despite loss of verbal language.
Occupational therapy improves daily living skills and hand function.
Nutritional support addresses feeding difficulties and prevents malnutrition.
Behavioral therapy assists in managing anxiety and repetitive hand movements.

Prevention

Pharmacological Prevention

none

Non-pharmacological Prevention

Genetic counseling for families with known MECP2 mutations to inform reproductive decisions.
Early intervention programs including physical, occupational, and speech therapy to maximize functional abilities.

Outcome & Complications

Complications

Recurrent respiratory infections due to impaired swallowing and aspiration risk.
Severe scoliosis causing restrictive lung disease.
Status epilepticus from uncontrolled seizures.
Malnutrition secondary to feeding difficulties.

Short-term Sequelae	Long-term Sequelae
Loss of motor skills and hand function. Onset of seizures and breathing irregularities. Developmental regression with cognitive decline.	Severe intellectual disability with profound communication impairment. Permanent motor disability including inability to walk. Chronic respiratory problems from aspiration and scoliosis. Progressive scoliosis and musculoskeletal deformities.

Differential Diagnoses

Rett Syndrome versus Angelman Syndrome

Rett Syndrome	Angelman Syndrome
Regression of purposeful hand use with hand-wringing stereotypies and loss of speech.	Severe developmental delay with happy demeanor, frequent laughter, and ataxic gait.
Normal early development followed by progressive microcephaly and autonomic disturbances.	No regression of acquired skills; symptoms are present from infancy.
Absence of the characteristic happy demeanor and frequent laughter seen in Angelman syndrome.	Characteristic prolonged episodes of laughter and seizures starting early in life.

Rett Syndrome versus Autism Spectrum Disorder (ASD)

Rett Syndrome	Autism Spectrum Disorder (ASD)
Normal early development followed by regression of speech and purposeful hand use between 6-18 months.	Early onset of social communication deficits and repetitive behaviors without a preceding period of normal development.
Presence of characteristic hand-wringing stereotypies and loss of hand skills.	Lack of hand-wringing stereotypies and instead presence of other repetitive behaviors like hand-flapping or rocking.
Deceleration of head growth (microcephaly) after initial normal growth.	No significant loss of purposeful hand skills or acquired motor skills after initial development.

Rett Syndrome versus Cerebral Palsy (CP)

Rett Syndrome	Cerebral Palsy (CP)
Normal early development followed by regression of motor and communication skills.	History of perinatal brain injury or prematurity with persistent motor deficits from birth.
Presence of hand-wringing stereotypies and loss of purposeful hand use.	Spasticity or hypertonia without a period of normal development or regression.
Progressive microcephaly and autonomic dysfunction are typical.	No characteristic hand stereotypies or loss of purposeful hand use.