10 Key Symptoms of Rett Syndrome: Early Warning Signs and Progression

Rett syndrome is a rare genetic neurological disorder that primarily affects girls and leads to severe impairments in virtually all areas of life. The condition typically appears after a period of normal early development, usually between 6 to 18 months of age. Understanding the symptoms of Rett syndrome is crucial for early recognition and intervention, which can help improve quality of life for affected individuals and their families.

This progressive disorder impacts brain development and affects motor skills, communication abilities, and cognitive function. While symptoms can vary in severity from person to person, there are distinctive patterns that characterize Rett syndrome. Below, we outline the 10 key symptoms that parents, caregivers, and healthcare providers should be aware of.

1. Loss of Purposeful Hand Skills

One of the hallmark symptoms of Rett syndrome is the loss of purposeful hand use that was previously acquired. Children who could once grasp toys, feed themselves, or point at objects gradually lose these abilities, typically between 12 to 18 months of age.

This regression is often one of the first noticeable signs that concern parents. The child may have developed normal fine motor skills during infancy but then begins to lose the ability to manipulate objects intentionally. This symptom is particularly distinctive because it represents a clear regression from previously attained developmental milestones.

As purposeful hand movements disappear, they are often replaced by repetitive, stereotypical hand movements, which is another characteristic feature of the syndrome.

2. Repetitive Hand Movements

Perhaps the most recognizable symptom of Rett syndrome is the development of repetitive, stereotypical hand movements. These movements typically replace purposeful hand use and can include:

• Wringing or squeezing motions
• Clapping or tapping
• Hand-to-mouth movements
• Washing or rubbing gestures
• Patting movements

These hand movements are nearly constant during waking hours and are involuntary in nature. The specific pattern of hand movements can vary from person to person, but they remain remarkably consistent for each individual. These stereotypies are so characteristic of Rett syndrome that they are considered a diagnostic criterion for the condition.

The hand movements often intensify during periods of stress, excitement, or fatigue, and may temporarily decrease when the individual is calm or engaged in an activity they enjoy.

3. Impaired Communication and Language Skills

Children with Rett syndrome experience significant difficulties with communication and language development. Initially, many children develop some language skills during their first year of life, including babbling and possibly a few words. However, these skills are progressively lost as the syndrome manifests.

The communication impairment in Rett syndrome is multifaceted:

Verbal Communication: Most individuals with Rett syndrome lose the ability to speak or never develop functional speech. Those who do retain some words typically have a very limited vocabulary and struggle with articulation.

Nonverbal Communication: While verbal communication is severely affected, many individuals with Rett syndrome maintain the ability to communicate through eye gaze, facial expressions, and body language. Eye contact often remains strong and can be an important communication tool.

Receptive Language: Understanding of language may be better preserved than expressive abilities, though this varies considerably among individuals. Many can understand simple commands and familiar phrases even when they cannot respond verbally.

4. Motor Coordination Problems and Apraxia

Apraxia, the inability to perform motor functions despite having the physical capability, is a central feature of Rett syndrome. This neurological symptom affects both gross and fine motor skills, making intentional movements extremely difficult.

Individuals with Rett syndrome may experience:

• Difficulty initiating movement
• Problems with walking and balance
• Unsteady, wide-based gait
• Tremors and shakiness
• Difficulty coordinating movements

The apraxia can be so severe that even when a person knows what they want to do and has the physical strength to do it, their body doesn’t respond to their intentions. This can be extremely frustrating for individuals with Rett syndrome and is often misinterpreted as cognitive inability rather than a motor planning problem.

Over time, many individuals lose the ability to walk independently or never acquire this skill, requiring wheelchairs or other mobility aids for ambulation.

5. Breathing Irregularities

Abnormal breathing patterns are common in Rett syndrome and represent one of the most concerning symptoms for caregivers. These breathing problems typically occur only during waking hours and normalize during sleep.

Common breathing abnormalities include:

• Hyperventilation (rapid, deep breathing)
• Breath-holding episodes
• Apnea (pauses in breathing)
• Air swallowing (aerophagia)
• Irregular breathing rhythms

These breathing irregularities can be alarming to witness and may cause the individual to become lightheaded or experience changes in skin color due to oxygen fluctuations. The episodes can last from several seconds to minutes and may occur multiple times throughout the day.

While these breathing problems are generally not life-threatening, they can contribute to other health issues and may cause anxiety for both the individual and their caregivers. The breathing abnormalities are thought to result from dysfunction in the brainstem areas that control breathing.

6. Growth and Development Delays

Slowed growth is a significant characteristic of Rett syndrome that affects multiple aspects of physical development. These growth abnormalities typically become noticeable as the syndrome progresses.

Head Growth Deceleration: One of the diagnostic criteria for Rett syndrome is a deceleration of head growth, usually occurring between 5 months and 4 years of age. Children are typically born with normal head circumference, but the rate of head growth slows significantly, leading to microcephaly (smaller than normal head size).

Overall Growth: Many individuals with Rett syndrome are smaller than average in height and weight. Growth velocity is often reduced throughout childhood and adolescence.

Skeletal Development: Bone density may be reduced, increasing the risk of fractures. Scoliosis (curvature of the spine) develops in a high percentage of individuals with Rett syndrome, often becoming more pronounced with age.

Hand and Foot Size: The hands and feet are often small and may feel cold to the touch due to poor circulation.

7. Seizures and Epilepsy

Seizures affect a significant proportion of individuals with Rett syndrome, with estimates ranging from 60% to 80%. The seizures can begin at any age but most commonly start during early childhood.

The types of seizures experienced can vary widely and may include:

• Generalized tonic-clonic seizures (grand mal)
• Absence seizures (brief staring spells)
• Focal seizures (affecting one part of the brain)
• Myoclonic seizures (brief muscle jerks)
• Atypical seizure patterns that may be difficult to classify

Seizure management in Rett syndrome can be challenging because the disorder itself causes many movements and behaviors that can resemble seizure activity, making diagnosis complex. It’s important to distinguish between actual seizures and the repetitive movements or breathing irregularities characteristic of the syndrome.

The frequency and severity of seizures vary considerably among individuals, with some experiencing daily seizures while others have only occasional episodes. If seizures are suspected, medical evaluation is essential for proper diagnosis and management.

8. Sleep Disturbances

Sleep problems are extremely common in Rett syndrome, affecting the majority of individuals with the condition. These disturbances can significantly impact quality of life for both the affected individual and their families.

Common sleep-related issues include:

Night Waking: Frequent awakenings during the night are typical, with some individuals waking multiple times and having difficulty returning to sleep.

Irregular Sleep-Wake Patterns: The normal circadian rhythm may be disrupted, leading to unusual sleep schedules and difficulty establishing a regular routine.

Nighttime Screaming or Laughing: Some individuals experience episodes of screaming, laughing, or crying during the night without apparent cause.

Daytime Sleepiness: Poor nighttime sleep often results in excessive daytime sleepiness and fatigue.

Sleep Apnea: Breathing problems may extend into sleep, though they are generally less pronounced during sleep than during waking hours.

These sleep disturbances can begin at any stage of the disorder and may change in pattern over time. They contribute significantly to caregiver stress and fatigue.

9. Muscle Tone Abnormalities

Abnormalities in muscle tone are characteristic features of Rett syndrome and can affect the entire body. These tone problems typically evolve over time and can vary in presentation.

Hypotonia (Low Muscle Tone): Many individuals with Rett syndrome exhibit decreased muscle tone, particularly in early stages. This can result in a “floppy” appearance and contributes to delays in motor milestones such as sitting and standing.

Hypertonia (Increased Muscle Tone): Some individuals develop increased muscle stiffness and rigidity, particularly as they age. This can lead to reduced range of motion and contribute to the development of contractures (permanent shortening of muscles or tendons).

Mixed Tone: It’s common for individuals to have low tone in some muscle groups and increased tone in others. For example, the trunk may be hypotonic while the limbs are hypertonic.

Dystonia: Involuntary muscle contractions causing twisting movements or abnormal postures may develop, particularly affecting the hands, feet, and facial muscles.

These muscle tone abnormalities contribute to the movement difficulties characteristic of Rett syndrome and can impact posture, mobility, and comfort.

10. Autonomic Nervous System Dysfunction

Rett syndrome affects the autonomic nervous system, which controls automatic bodily functions. This dysfunction can manifest in various ways and may significantly impact daily life.

Temperature Regulation: Many individuals with Rett syndrome have difficulty regulating body temperature, with cold hands and feet being particularly common. They may not respond normally to environmental temperature changes.

Gastrointestinal Problems: Constipation is extremely common and can be severe. Other digestive issues may include gastroesophageal reflux, difficulty swallowing, and bloating due to air swallowing during breathing irregularities.

Cardiac Function: Some individuals experience heart rhythm abnormalities, including prolonged QT interval on electrocardiogram, which can potentially increase the risk of cardiac complications.

Circulation Issues: Poor peripheral circulation can lead to cold, bluish hands and feet, and some individuals experience episodes of sudden color changes in the extremities.

Unusual Responses to Pain or Stress: The autonomic response to pain or stress may be altered, with some individuals showing decreased sensitivity to pain or unusual responses to stressful situations.

Main Causes of Rett Syndrome

Rett syndrome has a well-established genetic cause that has been identified through extensive research. Understanding these causes is important for diagnosis, genetic counseling, and ongoing research efforts.

MECP2 Gene Mutation: The primary cause of Rett syndrome is mutations in the MECP2 (methyl-CpG-binding protein 2) gene, located on the X chromosome. This gene is responsible for producing a protein that plays a crucial role in regulating other genes and is essential for normal brain function and development. Mutations in MECP2 account for more than 95% of classic Rett syndrome cases.

Sporadic Mutations: In the vast majority of cases, the MECP2 mutation occurs spontaneously (de novo), meaning it is not inherited from either parent. The mutation typically occurs randomly in the father’s sperm cells. This explains why most cases of Rett syndrome appear in families with no prior history of the disorder.

X-Linked Dominant Pattern: Rett syndrome follows an X-linked dominant inheritance pattern. Because the mutation is on the X chromosome and is dominant, one mutated copy of the gene is sufficient to cause the disorder. This explains why Rett syndrome primarily affects females – males have only one X chromosome, and mutations in MECP2 are usually fatal in males before or shortly after birth. Females have two X chromosomes, and the presence of one normal copy can allow survival, though with significant symptoms.

Other Genetic Causes: While MECP2 mutations cause the majority of cases, mutations in other genes have been identified in individuals with Rett-like symptoms, including:

• CDKL5 gene mutations, causing early-onset seizure variant
• FOXG1 gene mutations, causing congenital variant
• Other rare genetic variations that can produce similar clinical presentations

X-Inactivation: In females with Rett syndrome, the severity of symptoms can be influenced by a process called X-inactivation. Since females have two X chromosomes, one is randomly inactivated in each cell. The ratio of cells with the normal X chromosome active versus those with the mutated X chromosome active can influence symptom severity.

Frequently Asked Questions

At what age do symptoms of Rett syndrome typically appear?

Rett syndrome typically appears after a period of apparently normal development. Most children show normal development for the first 6 to 18 months of life. Symptoms usually become noticeable between 12 and 18 months of age, when developmental regression begins. The characteristic hand-wringing movements and loss of purposeful hand skills typically emerge during this period.

Can Rett syndrome be diagnosed before symptoms appear?

Rett syndrome can potentially be identified through genetic testing even before symptoms appear, if there is a known family history or if testing is done for other reasons. However, because most cases occur sporadically without family history, the diagnosis is typically made based on clinical symptoms and then confirmed with genetic testing for MECP2 mutations. Prenatal diagnosis is possible if a mutation has been identified in the family.

Do all individuals with Rett syndrome have the same symptoms?

No, there is significant variability in the symptoms and severity among individuals with Rett syndrome. While certain features are characteristic and required for diagnosis (such as loss of purposeful hand skills and development of stereotypical hand movements), the specific combination of symptoms, their severity, and the rate of progression can vary considerably. Some individuals are more severely affected than others, and symptoms may present differently across the lifespan.

Why does Rett syndrome primarily affect girls?

Rett syndrome primarily affects girls because it is caused by mutations in the MECP2 gene on the X chromosome. Females have two X chromosomes (XX), so even with one mutated copy, they have a second X chromosome that can partially compensate. Males have only one X chromosome (XY), so a mutation in their single MECP2 gene is usually fatal before or shortly after birth. Rare cases of males with Rett syndrome or similar symptoms typically involve different genetic circumstances, such as having an extra X chromosome (XXY) or mutations in other genes.

Can symptoms of Rett syndrome improve over time?

Rett syndrome typically progresses through several stages. After the initial regression period, many individuals enter a phase where the rapid progression stabilizes. During this stabilization phase, some improvements may be seen, particularly in social engagement, eye contact, and emotional connection. Some motor skills may improve slightly. However, the condition remains lifelong, and most symptoms persist. The degree of stabilization and any improvements vary among individuals.

Is Rett syndrome the same as autism?

No, Rett syndrome is a distinct genetic disorder, although it shares some features with autism spectrum disorder. In the past, Rett syndrome was classified as part of the autism spectrum, but it is now recognized as a separate condition with a specific genetic cause. While both conditions can involve social and communication difficulties and repetitive behaviors, Rett syndrome has distinctive features including the specific pattern of development followed by regression, characteristic hand movements, and the identified genetic mutation in most cases.

How is Rett syndrome diagnosed?

Rett syndrome is diagnosed through a combination of clinical evaluation and genetic testing. Doctors assess whether the individual meets specific diagnostic criteria, which include the characteristic pattern of normal early development followed by regression, loss of purposeful hand skills, development of stereotypical hand movements, and other typical features. Genetic testing to identify MECP2 mutations confirms the diagnosis in most cases. A thorough neurological examination and developmental assessment are essential parts of the diagnostic process.

Are there different types or stages of Rett syndrome?

Yes, Rett syndrome typically progresses through four recognized stages. Stage I (Early Onset) occurs between 6-18 months with subtle slowing of development. Stage II (Rapid Destructive) usually occurs between 1-4 years with rapid regression of skills. Stage III (Plateau or Pseudo-Stationary) can last for years or decades with stabilization of symptoms and possible slight improvements. Stage IV (Late Motor Deterioration) involves declining mobility but relatively stable cognitive and communication abilities. Not all individuals progress through all stages in the same way, and some may not reach the later stages.

References:

• National Institute of Neurological Disorders and Stroke – Rett Syndrome Information
• Mayo Clinic – Rett Syndrome
• National Organization for Rare Disorders – Rett Syndrome
• GeneReviews – MECP2 Disorders
• International Rett Syndrome Foundation