Rett Syndrome: What is it? Stages, Symptoms, Causes, Risk Factors, Diagnosis and Possible Treatments

It is a unique postnatal neurodevelopmental disorder that affects girls almost exclusively and is noticed for the first time in childhood.

Although it can rarely occur in children, it is found in all racial and ethnic groups worldwide.

It is characterized by average early growth and development followed by a slowdown in expansion, loss of intentional hand use, distinctive hand movements, decreased brain and head growth, problems with walking, seizures, and intellectual disability.

The disorder was identified by Dr. Andreas Rett, an Austrian doctor who described it for the first time in a journal article in 1966.

It was not until after a second article on the disorder, published in 1983 by the Swedish researcher Dr. Bengt Hagberg, that the disease was generally recognized.

The course of Rett syndrome, which includes the age of onset and severity of symptoms, varies from one child to another.

However, before the symptoms begin, the child usually seems to grow and develop normally, although there are often subtle abnormalities even in early childhood, such as loss of muscle tone ( hypotonia ), difficulty feeding, and shaking movements of the muscles. Extremities.


Then, gradually, the mental and physical symptoms appear. As the syndrome progresses, the child loses the deliberate use of his hands and speaking ability.

Other early symptoms may include problems with crawling or walking and decreased eye contact. The loss of functional use of the hands is followed by compulsive hand movements, such as wringing and washing. The beginning of this period of regression is sometimes sudden.

Apraxia, the inability to perform motor functions, is perhaps the most severely disabling feature of Rett syndrome, which interferes with all body movements, including gaze and speech.

Children with Rett syndrome often exhibit autistic-like behavior in the early stages.

Other symptoms may include walking on the toes, trouble sleeping, wide gait, grinding teeth, and difficulty chewing.

Also slow down growth, seizures, cognitive disabilities, and breathing difficulties while awake, such as hyperventilation, apnea (breath retention), and air swallowing.

What are the stages of the disorder?

Scientists generally describe four stages of Rett syndrome. Stage I, called early-onset, usually begins between 6 and 18 months.

This stage is often overlooked because the disorder’s symptoms may be somewhat vague, and parents and doctors may not notice the subtle deceleration of development at the beginning.

The baby may show less eye contact and reduce interest in toys. There may be delays in gross motor skills, such as sitting or crawling.

It is possible that there is a run-off of hands and a decrease in the growth of the head, but not enough to attract attention. This stage usually lasts a few months but may continue for more than a year.

Stage II, or the rapid destruction stage, usually begins between 1 and 4 and can last for weeks or months.

Its onset can be rapid or gradual as the child loses manual skills and spoken language. The characteristic movements of the hand, such as wringing, washing, clapping, or hitting, as well as repeatedly moving the hands towards the mouth, often begin during this stage.

The child can hold the hands clasped behind the back or keep them at the sides, touching and releasing randomly. The movements continue while the child is awake but disappear during sleep.

Irregular breathing may occur as episodes of apnea and hyperventilation, although breathing generally improves during sleep. Some girls also show symptoms of autistic types, such as loss of social interaction and communication.

Walking can be unstable, and initiating motor movements can be difficult. The slow growth of the head is usually noticed during this stage.

Stage III, or the plateau or pseudo-stationary stage, usually begins between 2 and 10 years and can last for years. Apraxia, motor problems, and seizures are prominent during this stage.

However, there may be an improvement in behavior, with less irritability, crying, and autistic-like characteristics. A girl in stage III may show more interest in her environment, and her alertness, attention span, and communication skills may improve.

Many girls remain in this stage most of their lives.

Stage IV, or the stage of deterioration of the late engine, can last for years or decades. Prominent features include reduced mobility, the curvature of the spine ( scoliosis ) and muscle weakness, stiffness, spasticity, and increased muscle tone with the abnormal posture of an arm, leg, or upper body.

Girls who could walk before can stop walking. Cognition, communication, or manual skills do not generally decrease in stage IV. The repetitive movements of the hand can reduce, and the look usually improves.

What are the symptoms of Rett syndrome?

Children with Rett syndrome have a wide variety of symptoms and a variety of physical and mental deficiencies. Symptoms may include:

  • It significantly impaired communication and cognitive (thinking) skills.
  • Loss of the ability to speak.
  • Symptoms of autistic types include social withdrawal or withdrawal and reduced eye contact.
  • Compulsive movements of the hand, such as wringing hands, clasping hands, clapping hands, or repeatedly moving the hands towards the mouth.
  • Loss of motor skills, such as walking or crawling.
  • Breathing problems, including breath retention and hyperventilation.
  • Gastrointestinal issues, such as reflux and constipation.
  • Problems with sleep.
  • Abnormal heart rhythms, such as prolonged QT syndrome.
  • Scoliosis and or kyphosis.
  • Microcephaly (small head size)
  • Low muscle tone
  • Irritability or agitation.
  • Grinding teeth ( bruxism ).
  • Difficulty chewing and swallowing

Slow Growth

The first known signs of Rett syndrome begin at six months of age. Before that, the baby will look like any other healthy baby. Typically, Rett syndrome will be discovered in the first two years of the child’s life.

The symptoms may progress slowly or appear pretty quickly, as they vary in all children.

The most common is seeing some of the symptoms between 12 and 18 months. This is a vital moment for a baby’s growth, both physically and mentally. Patients with Rett Syndrome Physically have stunted growth.

Increasingly clear as the child grows, those with the condition tend to be short and have low weight.

Small head

When a baby’s brain does not grow properly, the head will not increase in size. Head measures in infants and children are taken until they are 2 or 3 years old when they are on regular appointments with the doctor.

Microcephaly will be considered if the child’s head falls below a certain average point. Microcephaly is the general name for the condition of a small charge in babies, but there are many causes.

About Rett Syndrome, the mutated gene is found in the protein, which is necessary for developing the brain and nervous system. Small brain growth also affects the slow development of bodies.

Loss of hand movement

Between the ages of 1 and 4 years, children with Rett Syndrome will typically lose the use of their hands. In addition to the loss of the voluntary motor skills of the writing, they can also develop other habitual movements of the hand, often associated with other autistic conditions.

These repetitive movements manifest themselves in actions such as wringing hands or washing hands, sometimes clapping or banging or buckling. This condition phase can last a long time when the patient is in adolescence.

These physical manifestations may improve slightly over time, but they will be with them for the rest of their lives.

Loss of language skills

Children with Rett Syndrome generally lose their ability to speak between ages 1-4. This is the beginning of a communication closure in their bodies.

The gray matter in the MECP2 gene, responsible for everything related to movement, cognitive, sensory and emotional, motor and autonomic, affects your brain and the ability to create the correct sounds with your mouths and vocal cords.

By finding other ways to communicate without speaking, they will develop some nonverbal communication skills over time.

What are the causes of Rett syndrome?

Rett syndrome results from disease-causing changes in the MECP2 gene located on the long arm of the X chromosome.

This gene produces a protein called methyl-CpG, two binding proteins essential for brain development and is thought to be involved in controlling the function of other genes.

This protein is essential for the proper functioning of nerve cells and communication between neurons (brain cells).

The specific work of the protein is still not well understood. However, the adverse changes in the gene lead to the symptoms of Rett syndrome.

Rett syndrome occurs more frequently due to a sporadic or recent change in the MECP2 gene that was not inherited from the child’s parents.

Is Rett syndrome an autism spectrum disorder?

In the previous version of the Diagnostic and Statistical Manual of Mental Disorders, the DSM-IV (published in 1994), Rett syndrome was classified as one of the autistic spectrum disorders (ASD).

The other disorders of the autistic spectrum include Asperger’s syndrome, generalized unspecified developmental disorder, and childhood disintegrative disorder.

The DSM-5 in May 2013 no longer includes Rett syndrome, specifically an ASD.

Using this edition, specific syndromes such as Rett syndrome with autistic features are not grouped under the new general diagnosis of autistic spectrum disorder. Still, they are classified by their particular diagnostic code, which already exists for most genetic syndromes.

While Rett syndrome may not officially be an ASD in the DSM-5, the link to autism remains. Many children are diagnosed as autistic before the MECP2 mutation is identified, and then the diagnosis is reviewed at RTT.

Autistic traits occur, especially during regression, and sometimes these traits persist. Using the new DSM-5, many children are expected to have dual diagnoses of RTT and autism spectrum disorder.

Almost all cases of Rett syndrome are caused by a mutation in the methyl CpG 2 binding protein, or MECP2 gene (pronounced meck-pea-two gene).

Scientists identified the gene, which is believed to control the functions of many other genes, in 1999.

The MECP2 gene contains instructions for synthesizing a protein called methylcytosine two binding protein (MeCP2), which is necessary for brain development and acts as one of the many biochemical switches that can increase gene expression or tell other genes when they go out.

Because the MECP2 gene does not work correctly in individuals with Rett syndrome, insufficient amounts or structurally abnormal forms of the protein are produced and can cause the strange expression of other genes.

Not everyone who has a MECP2 mutation has Rett syndrome. Scientists have identified mutations in the CDKL5 and FOXG1 genes in individuals with atypical or congenital Rett syndrome but are still learning how those mutations cause the disorder.

Scientists believe that the remaining cases may be caused by partial deletions of genes, mutations in other parts of the MECP2 gene, or additional genes that have not yet been identified and continue to look for other causes.

Is Rett syndrome inherited?

Although Rett syndrome is a genetic disorder, less than 1 percent of registered cases are inherited or passed from one generation to another.

Most cases are spontaneous, which means that the mutation occurs randomly.

However, in some families of people affected by Rett syndrome, other women members of the family have a mutation of their MECP2 gene but do not show clinical symptoms. These women are known as “asymptomatic carriers.”

Risk factor’s

It is estimated that Rett syndrome affects one in every 10,000 to 15,000 births of living women and all racial and ethnic groups worldwide.

Prenatal testing is available for families with an affected daughter with an identified MECP2 mutation. However, since the disorder occurs spontaneously in most affected people, the risk of a family having a second child with the disease is less than 1 percent.

Genetic testing is also available for sisters of girls with Rett syndrome who have an identified MECP2 mutation to determine if they are asymptomatic carriers of the disorder, which is an infrequent possibility.

The MECP2 gene is found on a person’s X chromosome, one of the two sex chromosomes. Girls have two X chromosomes, but only one is active in a particular cell.

This means that in a girl with Rett syndrome, only a part of the cells of the nervous system will use the defective gene. Some of the child’s brain cells use the healthy gene and express average amounts of protein.

The severity of Rett syndrome in girls is, in part, a function of the percentage of their cells that express a standard copy of the MECP2 gene.

If the active X chromosome carrying the defective gene is deactivated in many cells, the symptoms will be mild. Still, if a more significant percentage of cells have the X chromosome with the normal MECP2 gene turned off, the onset of the disorder may occur earlier, and the symptoms can be more severe.

The story is different for children who have a MECP2 mutation that is known to cause Rett syndrome in girls.

Because children have only one X chromosome (and one Y chromosome), they lack a backup that can compensate for the defective one and have no protection against the harmful effects of the disorder.

Children with this defect often do not show clinical features of Rett syndrome but experience serious problems when they are born and die shortly after birth.

A few children may have a different mutation in the MECP2 gene or a sporadic mutation after conception that may cause some degree of intellectual disability and developmental problems.

How is Rett syndrome diagnosed?

Clinicians clinically diagnose Rett syndrome by observing signs and symptoms during the child’s early growth and development and continually assessing the child’s physical and neurological status.

Scientists have developed a genetic test to complement the clinical diagnosis, which involves searching for the MECP2 mutation in the child’s X chromosome.

A pediatric neurologist, a clinical geneticist, or a developmental pediatrician should be consulted to confirm the clinical diagnosis of Rett syndrome.

The doctor will use a particular set of guidelines divided into three types of clinical criteria: main, support, and exclusion. The presence of any of the exclusion criteria negates the diagnosis of classic Rett syndrome.

Examples of primary diagnostic criteria or symptoms include partial or complete loss of manual skills acquired, partial or total loss of acquired spoken language, and repetitive hand movements (such as wringing or squeezing, clapping, or rubbing).

Also, gait abnormalities include toes, walking or unsteady gait, broad base, and stiff legs.

Support criteria are not necessary for the diagnosis of Rett syndrome but may occur in some people. In addition, these symptoms, which vary in severity from one child to another, may not be seen in very young girls but may develop with age.

A child with support criteria but none of the essential criteria does not have Rett syndrome.

Support criteria include:

  • Scoliosis.
  • I am grinding small, cold hands and feet about height.
  • Abnormal sleep patterns.
  • Abnormal muscle tone.
  • Inappropriate laughter or shouting.
  • Intense eye communication.
  • Decreased response to pain.

In addition to the main diagnostic criteria, several specific conditions allow doctors to rule out a diagnosis of Rett syndrome.

These are known as exclusion criteria. Children with the following criteria do not have Rett syndrome: brain injury secondary to trauma, neurometabolic disease, a severe infection that causes neurological problems, and highly abnormal psychomotor development in the first six months of life.

There is no cure for Rett syndrome. The treatment for the disorder is symptomatic, focusing on the treatment of symptoms, and support, which requires a multidisciplinary approach.

Medication may be necessary for respiratory irregularities and motor difficulties, and anticonvulsant medications may be used to control seizures.

There should be regular monitoring of scoliosis and possible cardiac abnormalities. Occupational therapy can help children develop the skills needed to perform self-directed activities (such as dressing, feeding, and practicing arts and crafts), while physiotherapy and hydrotherapy can prolong mobility.

Some children may need special equipment and devices, such as braces to stop scoliosis, splints to modify hand movements, and nutritional programs that help them maintain a good weight.

Exceptional academic, social, vocational, and support services may be required in some cases.

What is the prognosis for people with Rett syndrome?

Despite the difficulties with symptoms, many people with Rett syndrome continue to live until middle age and beyond.

Because the disorder is rare, very little is known about long-term prognosis and life expectancy. Although there are women between 40 and 50 years with the disease, it is currently not possible to make reliable estimates of life expectancy beyond 40 years.

What research is being done?

Within the federal government, the National Institute of Neurological Disorders and Stroke (NINDS), the National Institute of Child Health Eunice Kennedy Shriver and Human Development (NICHD), and the Rare Diseases Research Office (ORDER) support clinical and basic research on Rett syndrome.

Understanding the cause of this disorder is necessary to develop new therapies to control specific symptoms and provide better diagnostic methods.

The discovery of the primary gene for Rett syndrome (MECP2) in 1999 provides a basis for additional genetic studies. It allows the use of recently developed animal models such as transgenic mice deficient in MECP2.

These mice have neurological abnormalities that can be reversed by activating the MECP2 gene later in life.

A study supported by NINDS searches for mutations in the MECP2 gene of individuals with Rett syndrome to learn about the function and dysfunction of the MeCP2 protein.

The information in this study will increase the understanding of the disorder and can lead to new therapies.

Another investigation aims to identify the molecular pathways affected by dysfunction, the development of animal models of the disorder, and therapy development in the initial stage.

Some researchers suggest that the specific type of mutation in the MECP2 gene affects the severity of Rett syndrome symptoms.

Studies are currently underway to understand each mutation that can cause the characteristics of Rett syndrome and how these mutations could change the features of the syndrome.

A study funded by the NIH on the natural history of Rett syndrome should also provide new information on these issues.

Scientists know that the lack of a properly functioning MeCP2 protein alters the function of mature brain cells, but they do not understand the exact mechanisms by which this happens.

Possible treatments

Researchers are trying to find other genetic switches that work similarly to the MeCP2 protein. Once they discover how the protein works and locate similar buttons, they can devise therapies to replace the malfunctioning switch.

Another result could involve the manipulation of other biochemical pathways to compensate for the malfunction of the MECP2 gene, which prevents the progression of the disorder. Gene therapy to achieve the regulated expression of a normal MECP2 gene is also under study in animal models.

The researchers are also trying to find other genes involved in Rett syndrome. Some studies have helped reduce the search for these genes, but much is still unknown about how these genes can cause or contribute to Rett syndrome.