Rett Syndrome: Comprehensive Guide

Overview

Rett Syndrome is a severe neurodevelopmental disease with X-linked inheritance and an incidence of 1/10,000-20,000. It is characterized by the loss of acquired motor and speech skills and meaningful hand movements after a normal or near-normal development period in the first 6 to 12 months of life, accompanied by stereotypic hand movements, walking disorder, and developmental delay.

Clinical Symptoms

Regression Period

Regression is mostly rapid, can be seen within weeks-months, and during this period:

• Autism symptoms
• Poor eye contact
• Severe sleep disorder
• Irritability emerge

This regression period is followed by mild improvement and stabilization. Cases where the classic clinical picture is not observed are called atypical Rett Syndrome.

Relationship with Autism Spectrum Disorder

Rett syndrome, which was classified among pervasive developmental disorders together with autism in DSM-IV TR, has not been included in the disorders in the neurodevelopmental disorders group in DSM-5.

Common Symptoms

Although some common symptoms are seen clinically in both disorders, Rett syndrome also has some differences from Autism Spectrum Disorder (ASD):

• Loss of language skills and social communication skills around 6-18 months
• Social, communication limitations and repetitive movements

Differences

• Regression is more prominent in Rett syndrome
• Findings such as walking disorder and microcephaly accompany
• Hand stereotypies are frequently and commonly observed
• Purposeful hand use is impaired

Genetic Foundations

MECP2 Gene Mutations

• 95% of patients with typical Rett Syndrome
• 73.2% of patients with atypical Rett Syndrome have mutations in the MECP2 gene

Almost all mutations are sporadic. Base substitution (truncating) mutations in R168X, R255X, and R270X, large insertions and deletions cause more severe phenotypes.

Other Genes

MECP2 mutation is not detected in 3-5% of patients with Rett Syndrome. CDKL5 and FOXG1 are other genes that can cause atypical Rett Syndrome. These genes should be considered in early-onset, epileptic, or microcephalic male children.

Epilepsy and Neurological Findings

Epilepsy Frequency

Epilepsy has been reported in 60-80% of patients with Rett Syndrome. Epilepsy incidence is higher in early-onset Rett Syndrome patients and is accompanied by more severe motor retardation.

Seizure Types

• Most common: Complex partial seizures and generalized tonic-clonic seizures
• Rarer: Absence and clonic seizures
• Febrile seizures are more common in patients with Rett Syndrome

Prognostic Criteria

• Seizures appear earlier in Rett syndrome patients without MECP2 mutation
• Early-onset seizures have a more resistant course
• Seizures starting after 5 years of age are considered a good prognostic criterion

Incorrect Seizure Assessment

The following patterns in Rett Syndrome patients can be incorrectly evaluated as seizures:

• Hand stereotypies
• Breath holding and cyanosis
• Hyperventilation and chaotic breathing pattern
• Eye movements
• Oral-facial dyskinesia

Timing and Stages

MECP2 Mutation Positive Patients

Epileptic seizures occur in stages 2 and 3 of the disease, mostly between 7 and 12 years of age.

CDKL5 Mutation Positive Patients

50% of seizures are in the form of infantile spasms.

EEG Findings

Early Period

In classic Rett Syndrome, EEG is typically normal in the early period. Focal epileptic discharges in the centrotemporal region can be seen along with motor symptoms and sleep problems.

Advanced Stages

On EEG:

• Impaired sleep organization
• Bilateral synchronized burst pseudoperiodic delta activity
• Generalized rhythmic spike-wave discharges are seen

Final Stage

In the final stage of the disease, seizures are no longer a prominent feature.

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