What is Rett Syndrome?

Rett Syndrome is a rare, genetically-based neurodevelopmental disorder that primarily affects girls. Development typically proceeds normally during the first few months after birth, but regression in acquired motor, language, and social skills occurs between 6 and 18 months of age. Loss of hand skills, repetitive hand movements, communication difficulties, and impaired movement coordination are among the distinguishing features of the syndrome. Rett Syndrome is most commonly associated with mutations in the MECP2 gene and requires lifelong specialized support and a multidisciplinary approach.

Rett Syndrome is not a neurodegenerative disease, even though it appears to be progressive; it is considered more of a condition that affects brain development. The clinical picture becomes apparent during childhood, and the severity of symptoms may vary between individuals. The disease is generally defined in four clinical stages, which may include periods of developmental regression, stabilization, and partial improvement.

Common symptoms of the syndrome include limited or no development of speech skills, balance and walking difficulties, breathing irregularities (hyperventilation, breath-holding), epileptic seizures, muscle tone abnormalities, and scoliosis. However, eye contact and emotional awareness are relatively preserved in many individuals, which is considered an important strength for social interaction.

Although there is no definitive cure for Rett Syndrome, early diagnosis and individually tailored physical therapy, occupational therapy, speech therapy, and psychosocial support play an important role in improving quality of life. Family education and long-term follow-up are essential for supporting the child's development and reducing the burden on caregivers.

What Causes Rett Syndrome?

Rett Syndrome is mostly caused by mutations in the MECP2 (Methyl-CpG-binding protein 2) gene. This gene plays a critical role in the maturation and regulation of nerve cell function during early brain development. Defects in the MECP2 gene affect communication between nerve cells, leading to the neurodevelopmental symptoms characteristic of Rett Syndrome.

A significant proportion of Rett Syndrome cases develop as a result of spontaneous (de novo) mutations; that is, the mutation does not come from the mother or father, but arises spontaneously during embryonic development. For this reason, there is often no family history. The reason the syndrome is more common in girls is that the MECP2 gene is located on the X chromosome. In males, this mutation is generally more severe and may be incompatible with life in the early stages.

In rare cases, genetic mechanisms such as X chromosome inactivation may affect the severity of symptoms. Even in individuals with the same genetic mutation, differences in the clinical picture are attributed to this situation. In summary, Rett Syndrome is a condition caused primarily by genetic and molecular changes, not environmental factors.

What Are the Symptoms of Rett Syndrome?

Symptoms of Rett Syndrome typically appear after the first 6–18 months of life and are characterized by the gradual loss of some skills previously acquired by the child. The type and severity of symptoms may vary between individuals; however, some clinical findings are distinctive.

Common Symptoms

• Loss of hand skills and replacement with repetitive hand movements
• (hand rubbing, hand flapping, clenching, bringing to the mouth)
• Stagnation or regression in speech and language development
• Decreased social interaction, although eye contact is often maintained
• Walking and balance problems, ataxic or stiff gait
• Muscle tone disorders (hypotonia or spasticity)

Neurological and Physical Symptoms

• Epileptic seizures
• Respiratory irregularities
• (breath holding, hyperventilation, irregular breathing)
• Microcephaly (slowed growth of head circumference)
• Scoliosis and other orthopedic problems
• Cold hands and feet, circulation problems
• Behavioral and Sensory Characteristics
• Repetitive behaviors
• Sleep problems
• Sensory sensitivities
• Anxiety-like reactions or periods of restlessness

Although cognitive abilities in Rett Syndrome often appear to be severely affected, individuals' comprehension capacity may be higher than what they express. Therefore, accurate assessment and supportive approaches are of great importance. What Are the Stages of Rett Syndrome?(H2)

Rett Syndrome is generally examined in four stages in terms of its clinical course. Although these stages are not clearly defined, they provide guidance on the onset and progression of symptoms. The duration and severity of each stage may vary from person to person.

Stage 1: Early Onset (Quiescent Stage)

• Begins between 6 and 18 months
• Development slows down, but this may not be noticeable
• Eye contact and social interest may decrease
• Mild delays in motor development may be observed
• Head circumference growth begins to slow
• This stage often goes unnoticed.

Stage 2: Rapid Regression Stage

• Occurs between 1 and 4 years of age.
• Significant loss in speech and hand skills becomes apparent.
• Purposeful hand movements disappear, replaced by repetitive hand movements.
• Social withdrawal and autistic-like behaviors may be observed.
• Respiratory irregularities and sleep problems begin.
• Symptoms become most pronounced at this stage.

Stage 3: Plateau Stage

• This stage can last until school age and adolescence.
• Regression stops, and partial improvement may be observed in some areas.
• Social interest and eye contact may increase.
• Seizures and motor problems may persist.
• Behavioral issues may decrease.
• This stage is the most productive period for education and therapeutic interventions.

Stage 4: Late Motor Deterioration Stage

• Begins after adolescence.
• Mobility decreases, and loss of walking ability may occur.
• Muscle stiffness, joint limitations, and scoliosis increase.
• Cognitive and communication skills generally do not deteriorate further.
• Social awareness can be largely preserved even as motor difficulties increase.

How is Rett Syndrome Diagnosed?

The diagnosis of Rett Syndrome is a multifaceted process based on a detailed assessment of the child's developmental process, including clinical observation and genetic testing. The disease is usually recognized in children who show normal development in the first months of life, with developmental regression appearing after 6–18 months. Loss of purposeful hand skills, regression in speech and communication, repetitive hand movements, and motor problems are among the key findings that guide the diagnostic process. To reach a definitive diagnosis, clinical signs are supported by genetic testing, and a differential diagnosis is made from similar neurodevelopmental disorders.

The first and most important step in this process, which forms the basis of the diagnosis, is clinical evaluation. A detailed review of the child's developmental history from birth, along with an examination of the timing and nature of the regression in acquired skills, is of great importance for diagnosis. In this context, certain key clinical criteria are considered guiding factors in the diagnosis of Rett Syndrome.

1. Clinical Evaluation

The most important step in diagnosis is a detailed examination of the child's developmental process. The following basic clinical criteria are considered guiding principles for diagnosis:

A history of normal or near-normal early development,

• Developmental regression after 6–18 months,
• Loss of purposeful hand use,
• Emergence of repetitive hand movements,
• Significant regression in speech and communication skills,
• Walking and balance problems,
• The presence of these findings together strengthens the suspicion of Rett Syndrome.

2. Developmental and Neurological Examinations

• A neurological examination assesses muscle tone, reflexes, and motor skills.
• Developmental tests (motor, language, cognitive areas) may be administered.
• EEG may be used to investigate epileptic activity.
• Brain imaging (MRI) generally does not confirm the diagnosis but is used for differential diagnosis.

3. Genetic Tests

• MECP2 gene analysis is the most important laboratory method supporting the diagnosis.
• A MECP2 mutation is detected in the vast majority of cases.
• A negative result does not completely rule out Rett Syndrome if the clinical findings are strong.

4. Differential Diagnosis

• Rett Syndrome; · Autism spectrum disorder, · Cerebral palsy,
• Metabolic disorders,
• Other neurodevelopmental syndromes.

5. Importance of Early Diagnosis

Although early diagnosis does not change the course of the disease, it allows for the early initiation of appropriate therapy and education plans, informs and supports the family, and prevents secondary complications.

How is Rett Syndrome Treated?

The treatment of Rett Syndrome does not include a curative approach that completely eliminates the disease, but rather encompasses a long-term, multidisciplinary, and individualized process that aims to increase the individual's functionality, manage symptoms, and improve quality of life. The treatment plan requires collaboration between pediatric neurology, physical therapy and rehabilitation, occupational therapy, speech and language therapy, psychology, special education, and, when necessary, orthopedics and nutrition specialists.

Pharmacological treatment is not intended to cure Rett Syndrome; it is used to control symptoms such as epileptic seizures, muscle tone disorders, respiratory irregularities, sleep problems, and anxiety-like

and is carefully tailored for each individual. In addition, physical therapy started early on helps maintain muscle strength and range of motion and prevent scoliosis and joint contractures, while occupational therapy focuses on supporting daily living skills and maintaining purposeful hand use to the extent possible.

Even if speech abilities are severely limited, alternative and augmentative communication methods (eye-gazing, picture cards, technological communication devices) play a crucial role in increasing the individual's interaction with their environment. Psychological support and special education practices play a critical role in understanding the individual's emotional needs, behavioral adjustments, and maximizing their learning potential. At the same time, psychoeducation and counseling services for the family are an integral part of treatment in terms of reducing the burden of care, strengthening coping skills, and making the long-term care process sustainable. Although current research focuses on genetic and targeted treatments, the most effective approach in Rett Syndrome management today is early diagnosis, continuous follow-up, and a holistic support approach.

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