Frequently asked questions

Diagnosis

Is Rett syndrome an autism spectrum disorder?

Rett syndrome is no longer classed as an autism spectrum disorder. However, children and adolescents with Rett syndrome can show some features of autism. These features are especially evident during the period of regression when children typically close off from social contact. At the end of regression many children become more sociable and seek social contact once again. For some, however, autistic features persist. A communication disorder is also part of Rett syndrome, as it might be in autism spectrum disorders.

Bernd Wilken
SAB Member

Development seemed so normal. What happened?

The great majority of individuals with Rett syndrome carry a pathogenic variant in the MECP2 gene, which occurred at the time of conception. MECP2 regulates the pattern necessary for proper development of the central nervous system. Although infants with Rett syndrome appear normal at birth and during the first months of life, we currently think that the effect of the genetic alteration begins early in fetal life and expresses later clinically.

Aglaia Vignoli
SAB member

Since skills are lost, is Rett syndrome degenerative?

Rett Syndrome is considered a neurodevelopmental disorder that means the disorder always begins in childhood with difficulties with language and speech, motor skills, behavior, and learning. The symptoms often change or evolve as a child grows older, but some limitations are permanent.

Individuals with Rett syndrome can learn throughout their lives and some skills may improve during growth, while others may get worse. A lot of people with Rett syndrome become adults and their prolonged survival is related to careful planning for long-term care and improved clinical management.

Aglaia Vignoli
SAB member

How does my child get diagnosed?

There are different paths which can lead to a diagnosis of Rett syndrome.

The diagnosis is often given by a physician/paediatrician when your child has symptoms seen in classical Rett syndrome. These symptoms are loss of learned skills especially of hand function and language, and then the development of hand movements called hand stereotypies. There are clinical diagnostic criteria which can be used if the physician/paediatrician or others with knowledge of Rett syndrome is suspected. The next step will be a genetic testing of the gene MECP2 which is known to cause Rett syndrome.

The diagnosis can also be given at a younger age before the classical symptoms are obvious. For some children there may be a suspicion of a muscular disease, autism or developmental delay without thoughts of a specific condition. This might lead to a broader genetic testing using Next Generation Sequencing (exome/genome) where many/all genes are investigated. This screening might reveal a variant in MECP2. These children are very young maybe under 6-12 months of age.

Some children get the diagnosis when they are older after a genetic screening. This might be the case if your child has symptoms at the milder end of the Rett syndrome spectrum, so no one had previously suspected that your child could have Rett syndrome. Perhaps because of some developmental delay and maybe co-existing medical issues such as epilepsy, Next generation Sequencing (exome/genome) is done and a MECP2 variant turns up.

Anne Marie Bisgaard
SAB member

What do I do when my child is diagnosed?

Many questions arise when a child is diagnosed with Rett syndrome.

There is a lot of information on the internet about the syndrome, how it affects children and what you must be aware of. But there will also be a need for more specific knowledge of Rett syndrome and the impact it has on your child and on your family life. Hopefully, you will get the opportunity to talk with a physician, a paediatrician and/or therapists who have experience in the syndrome. They can counsel you and help you with planning for the future medical needs as well as everyday care, the best day care or school facility and the best training/rehabilitation to help with motor function, learning and communication.

Your child will need regular medical follow-ups at a paediatric department. You might also need to talk with a clinical geneticist who can counsel you regarding the genetic basis for the syndrome and the recurrence risk in future pregnancies.

Anne Marie Bisgaard
SAB member

Medical conditions and care

What are the most common gastrointestinal issues?

Gastrointestinal issues are common in Rett syndrome. The most common are constipation, abdominal bloating and gastrointestinal reflux (GERD). Signs of constipation might be lumpy or hard stools, fresh blood on stools, stomach cramp, bloating, painful defecation and/or less than 3 defecations a week. It can be alleviated by optimising fluid and fiber intake, by being as physically active as possible, having good toilet habits and by using laxative agents after medical input and advice if needed. Bloating can be due to air swallowing with or without episodes of hyperventilation/breath holding, physical inactivity, intake of air producing foods or constipation. It is, unfortunately, often difficult to treat. Medical treatment is often disappointing but physical activity can help. It is possible to release air from a gastrostomy tube if present. GERD might present with symptoms such as vomiting, rumination, regurgitation, coughing but can be difficult to detect. Investigation and treatment are as for the general population.

Anne Marie Bisgaard
SAB member

What causes breathing disturbances?

Different types of breathing dysfunction can occur in Rett syndrome and they can have different causes. Central apnoeas are most common when the person with Rett syndrome is awake, but can also happen during sleep. They occur when the brain stops generating effort to breathe (won’t breathe). Obstructive apnoeas are most common during sleep. Obstructive apnoeas occur when muscles in the throat relax and collapse causing a blockage of the airway, while there is still an effort to breathe (can’t breathe). Occasional apnoeas are very common even in neurotypical people. However, if they last longer than 10 seconds each, and more than 5 occur in an hour, clinical intervention may be required. Both types of apnoea can be followed by rapid and/or forceful breathing (hyperventilation). Central apnoeas are caused by abnormal communication between neurons located in the brainstem (the region of the brain that controls breathing muscles). Research suggests that, in Rett syndrome, brain cells (neurons and glia) either fail to make enough contacts (synapses) with other brain cells and/or do not release the right amounts of brain chemicals (neurotransmitters) when they are stimulated. Various different types of respiratory brain cells and chemicals are thought to be involved, making it difficult to treat. This problem also contributes to obstructive apnoeas, which can also be caused by various factors not necessarily related to Rett syndrome. Other common risk factors for obstructive sleep apnoeas include having large tonsils, adenoids, tongue or a small lower jaw; being overweight; taking certain sleeping tablets, anti-anxiety or some anti-epilepsy medications; having severe scoliosis; or being over 40 years of age.

Ana Abdala
SAB Member

What happens when they hyperventilate?

Hyperventilation is the word used to describe rapid and/or forceful breathing. It is a natural response to a disturbance in blood gases (O2 and CO2), to exercise, or to environmental stressors (anxiety). Hyperventilation naturally occurs after an apnoea, if it is long enough to disrupt blood gases. However, research in mouse models suggests that, in Rett syndrome, the hyperventilation response to an apnoea may be delayed, and when it occurs it is exaggerated, producing an overcorrection of blood gases. In some people with Rett, hyperventilation may also occur in the absence of apnoeas. These are likely to be linked to the brainstem abnormalities described above. In either case, undue hyperventilation can result in low levels of CO2 in the blood. This in itself can lead to apnoeas, as CO2 is an essential stimulus for breathing. To compound the problem, some people with Rett are thought to be more vulnerable to apnoeas that are induced by low blood CO2. This can lead to periodic breathing (consecutive periods of apnoeas interspersed with hyperventilation).

Ana Abdala
SAB Member

What happens when they hold their breath?

Breath-holding is an unhelpful label as research in mouse models of Rett demonstrated that the pauses in breathing are involuntary. In Rett syndrome, central apnoeas occur because the brain stops commanding breathing muscles to contract. When an apnoea occurs, blood levels of O2 will slowly drop, and CO2 will increase. At a certain level, these changes trigger protective reflexes that restart breathing and induce hyperventilation, to correct blood gases quickly. However, as described above, these protective reflexes are disrupted in people with Rett.

Ana Abdala
SAB Member

Will they always breathe this way?

The RTT Natural History Study identified that nearly all participants with classic or severe atypical Rett experienced breathing dysfunction at some point in their life. Whereas those with mild atypical Rett were less likely to experience breathing disturbance (6-7 out of 10). Central apnoeas may appear, become worse or improve, disappear or reappear at any stage of life. Obstructive sleep apnoeas are more common in people with Rett syndrome than in the general population but do not affect every person with Rett. Both types of apnoeas may improve with intervention (see below).

Ana Abdala
SAB Member

What should we do about their irregular breathing?

Obstructive apnoeas that occur during sleep may be easier to manage than central apnoeas. There are several management options, but no cure. Before a treatment can be indicated, the breathing dysfunction must be assessed. Your GP (family doctor) can provide a referral to specialist clinics that assess people with sleep breathing disorders. Treatment options will depend on the results of the assessment and may include: lifestyle changes (e.g., weight loss, management of anxiety); breathing aids (continuous positive airway pressure-CPAP or non-invasive assisted ventilation-NIV; supplemental O2 or rebreathing masks); or surgery (e.g., adenotonsillectomy, scoliosis). No drugs are licensed to treat breathing dysfunction in Rett syndrome. However, case studies showed that some drugs prescribed to treat anxiety or epilepsy improved breathing dysfunction in some individuals. A neurologist consultant may prescribe those drugs at their discretion. However, some drugs are not indicated in people with Rett who have abnormal heart rhythms (long QT interval). In this case, joint assessment by a cardiologist consultant is recommended.

Ana Abdala
SAB Member

Do breathing problems cause other health problems?

If left unmanaged, apnoeas have a significant negative impact on quality of life. They may further impair motor coordination, concentration, memory, mood and cause poor sleep. Large and frequent drops in blood oxygen may also increase the risk of abnormal heart rhythms which have been linked to sudden death. Abnormal blood gases can also cause muscle spasms that may be confounded with seizures. They can also trigger actual seizures. Only through clinical assessment, it can be determined if apnoeas are severe enough to warrant intervention.

Ana Abdala
SAB Member

Do all children with Rett syndrome have seizures?

Seizures are a very common problem in Rett syndrome, occurring in approximately 80% of individuals. Seizures can be either focal in origin or generalized. In most people the epilepsy is treatable. However, in around 15% of cases treatment is difficult and the epilepsy is resistant to anticonvulsant drugs. During aging epilepsy becomes less intrusive.

Bernd Wilken
SAB Member

Are the abnormal breathing episodes or tremors related to seizures?

Breathing abnormalities (e.g. hyperventilation attacks or apnoeas) are related to a disturbance of brainstem regulation. They are not a type of seizure activity. However, a seizure episode, even in people who do not have Rett syndrome, can sometimes affect the brainstem and cause apnoeas.

Tremors may be related to side effects of anticonvulsant drugs (e.g. valproic acid or lamotrigine) but may also be part of a Rett movement disorder. In some cases, muscle spasms can be caused by abnormal blood gases, particularly after a prolonged period of hyperventilation leading to significant hypocapnia (low blood levels of CO2).

Bernd Wilken
Ana Abdala
SAB members

Are children with Rett syndrome at a higher risk for sleep problems?

Sleep problems are a recognised feature of Rett syndrome, with many individuals experiencing sleep problems at some time in their life. These problems may result from a disturbance of regulation in melatonin release.

Bernd Wilken
SAB member

Should they have an electrocardiogram (ECG)?

It is recommended to have an ECG to exclude long QT syndrome at diagnosis and to consider it at follow-ups. The risk for this condition is not clear but it might be increased by some medication and if there is a breathing disorder.

Anne Marie Bisgaard
SAB member

Life with Rett Syndrome

What is the life expectancy of an individual with Rett syndrome?

According to the literature 25 years ago life expectancy of a woman with Rett syndrome was estimated at 49 years. At the moment longitudinal studies for males with Rett syndrome are lacking. Medical treatment has greatly improved since then, so we believe that life expectancy has also been extended. Survival into the fifth decade is typical in Rett syndrome with more than 70% of individuals surviving into middle age. However, there are some unexpected and unexplained deaths in younger ages.

Michelle Stahlhut
SAB Member

Can they gain some independent skills?

Individuals with Rett syndrome are dependent on help and support from others to do activities and to cope with everyday life. However, many can learn some independent skills such as eating and drinking what is served to them, to do movements from one position to another, and to make choices using hands or eye pointing. They will, however, need some guidance.

Anne Marie Bisgaard
SAB member

Which activities are possible for individuals with Rett syndrome?

Participation in physical activities and recreation can be considered as medicine to individuals with Rett syndrome. Each activity is blessed, and it should be done according to the abilities and interests of the individual with Rett.

But! Never underestimate the person with Rett syndrome, always try and push the limits. You might be surprised with what they can actually do.

Always consider meaningful activities that they enjoy. The individual may need physical assistance, aids or adapted equipment. Talk to the physical therapist to find ways to engage the individual in physical activities and recreation.

Meir Lotan
SAB Member

Can people with Rett speak?

One of the key features of Rett syndrome is loss of speech, meaning that if someone starts to speak a few words or short phrases as a toddler they will likely lose them during the period of regression. The loss may also include babbling or vocalisations. Some people with Rett syndrome will never speak at all; some will lose the words they had then learn to speak a few words again after regression; others will not lose their speech and will continue to use spoken words or short sentences throughout their lives. However, speech will never be the only way in which someone with Rett syndrome communicates. Everyone with Rett syndrome will need some form of AAC (Augmentative and Alternative Communication) to help them communicate.

Gillian Townend
SAB member

Does Rett syndrome affect intelligence?

In the past, all people with Rett syndrome were described as having severe cognitive impairments and not functioning at a level higher than an infant of 18 months. This was largely because traditional tests of language understanding and cognitive ability (intelligence) rely on motoric or verbal responses, two areas of difficulty in Rett syndrome. Through the increased use of eye tracking/eye gaze technology we are realising that people with Rett syndrome fall within a wide range of cognitive abilities (intelligence). It is important that caregivers do not set low expectations that stop opportunities for stimulation and learning. Providing appropriate communication and language support is important for maximizing cognitive abilities.

Gillian Townend
SAB member

Can children and adults with Rett syndrome learn?

Yes, they can. They can keep learning their whole life, especially communication and academic skills. It takes a lot of support and good teaching for academic skills but providing the right sorts of support and teaching can make a huge difference. Individuals have to work hard to show what they have learned, though, and it is important not to let that stop support persons from helping individuals learn.

Helena Wandin
SAB Member

What about school for my child?

The school system is different in every country and maybe every region. The school should work closely with the home and other important support persons to form shared goals and strategies.

Helena Wandin
SAB Member

How does Rett syndrome affect communications?

Rett syndrome affects communication in many ways. One of the key features of Rett syndrome is a loss of speech and, although there is some variation between individuals, most people with Rett syndrome do not use speech to communicate. Rather, they communicate through non-verbal means including body movements, facial expression and forms of AAC (Augmentative and Alternative Communication). However, communication through body language may also be affected by disturbances in motor movement and planning, for example, pointing at things, voluntary head, and even eye, movements. Some individuals do not display other than large emotions through facial expressions. In combination with breaks in attention, this may lead others to believe that they are not interested in interacting or in participating in an activity. It is therefore really important to know that they may still be interested and to keep a close watch on their eye gaze and look for small signals of attention.

Gillian Townend
SAB Member

Is everyone with Rett syndrome capable of communicating in some way?

Yes! All behavior is communication, whether intentional or not.

With the right support, all people with Rett syndrome can learn to communicate with intent using their eyes, body movements, some form of AAC (Augmentative and Alternative Communication), and very rarely speech. Levels of communication may vary from day to day, moment to moment depending on what’s happening in the person’s body but that doesn’t mean they can’t communicate, and all communication partners should expect that the person will be able to communicate, give them time, and support.

Gillian Townend
SAB Member

What is AAC? Are some forms of AAC more appropriate than others for someone with Rett syndrome?

AAC (Augmentative and Alternative Communication) means anything apart from, or as a support to, oral speech that we use to help us communicate our needs, wants, thoughts, and ideas. AAC can be unaided (facial expression, body language, gesture) or aided. Aided AAC includes low-tech forms (objects, photos, picture symbols used as individual items or on a communication board or book) and high-tech forms (something powered by batteries or electricity that has speech output). High-tech AAC covers a range from simple single message buttons to complex computers that can be activated by touchscreen, a switch or eye gaze.

Because of the motor movement and planning difficulties that are part of Rett syndrome any forms of AAC that rely on accurate hand use are never going to be the best options to use. Eye gaze is usually the best way for someone with Rett syndrome to communicate and to use AAC. This can be simple like eye pointing to objects or pictures to make a choice, or more complex, using the eyes to make vocabulary selections on an eye gaze controlled computer.

AAC systems should always be matched to the person and should be available throughout the day to support communication.

Gillian Townend
SAB Member

What is PODD?

PODD stands for Pragmatic Organization Dynamic Display. It is a specific sort of communication system that uses symbols and words to support communication throughout the day. It was developed by Gayle Porter, an SLP in Australia. In book form it can be used with direct access (by touching, pointing with a hand/finger) or Partner Assisted Scanning (PAS) where the communication partner reads the words aloud and the person with Rett syndrome responds with their own signal for yes or no. There are several options for layout and content depending on different stages of language development and different needs such as access and vision. People with Rett syndrome are most likely to use a PODD book with PAS or to use PODD on an eye gaze controlled computer.

Gillian Townend
SAB Member

What can I do as a communication partner to help my child?

A lot! You can support communication here and now, by noticing, valuing and responding to all communication, however small. And you can show them that you expect that they have something to say by waiting for their initiative or response when you are talking or doing something together. Any type of reaction or initiative is fine. You can also look for support to develop your child’s communication. This often involves introducing communication devices and using these yourself while speaking to your child. You can also inform others on how they can best communicate with your child and how they can help to develop your child’s communication and language. A communication passport or similar description that is individual to your child can help everyone to be a good communication partner.

Helena Wandin
SAB Member

How can I help my child to be more active or to keep active as they get older?

All of us, including individuals with Rett syndrome are creatures of habit. If you want the care receiver with Rett syndrome to be active, start when they are young.

When there is a regression (due to illness or other life events), there is a change in habits and in the daily routines. Let the individual acclimate to their new situation, and when appropriate regain the active daily routine.

All activities must be meaningful and motivating for the person with Rett syndrome. Don’t just exercise, make it interesting for them.

Michelle Stahlhut
SAB Member

In what ways can physical therapy help someone with Rett syndrome?

Physical therapy and physical activity can address all the limitations of the individual with Rett syndrome. The motor skills, mobility, joint range of motion, constipation, osteoporosis and participation in desired activities. Work together with the physical therapists to set goals and try and achieve those goals.

Meir Lotan
SAB Member

Can a child with Rett syndrome regain lost skills?

Yes! It is very easy for individuals with Rett syndrome to lose their abilities but if motivation is high and the therapy program is intensive, lost abilities can be regained (not all of them and not always).

Meir Lotan
SAB Member

What kind of difficulties will they have?

Individuals with Rett syndrome develop a number of limitations regarding both motor skills and communication. Apraxia, that means a difficulty in programming movements, is one of the most severe impacts of the disease, involving hand function, walking and speaking. It may be very difficult to make an accurate assessment of their development and intelligence, although new methods based on eye-tracking allow some kind of evaluation. Other problems that may decrease quality of life are epilepsy, sleep problems, breathing abnormalities, scoliosis and gastrointestinal discomfort.

Aglaia Vignoli
SAB member

Research

Is there a cure for Rett syndrome?

Therapies currently available for Rett syndrome are of very limited scope, so far, and are mainly directed towards alleviation of a few of the symptoms.

Since efforts to restore normal MECP2 levels progress slowly due to its extremely technical difficulty, many alternative therapeutic efforts aim to correct those cellular instructions that are altered as a consequence of mutations in MECP2, and which have the highest impact on the patients’ motor, respiratory and/or cognitive impairments. However, only a limited number of therapeutic strategies in these areas are reaching clinical trials, in part because we still have an incomplete picture of MECP2 function.

Sonia Guil
SAB Member

What has research taught us about Rett syndrome?

On one hand, research has taught us about the underlying genetic causes of Rett (in most cases, mutations in the MECP2 gene, but an increasing number of other potential genetic causes are being identified and in process of being validated). Identifying the genetic cause has helped to discriminate between syndromes that (partially) share the clinical manifestations but have distinct etiology to Rett syndrome, and thus deserve distinct investigation and treatment.

Once the genetic cause was found, experimental models have been developed over the last two decades to dissect MECP2 function and find therapeutic angles of intervention. One important advance was the realisation that, at least in experiments in mice, the disorder is reversible when normal MECP2 is restored in the brain, even in animals already presenting full symptomatology. Even though it is not clear whether this might directly represent the situation in humans, these findings provide great hope for families and researchers. In addition, we now know that restoring the appropriate levels of MECP2 protein (not too little, but not in excess, either) is key for recovering the physiological function, and many efforts are underway to achieve this specific window of activity in the affected cells.

Besides the thorough description of the clinical presentation of the syndrome, research has also revealed the key aspects of MECP2 function at the molecular, cellular, and circuitry level in the brain. We now know that Rett syndrome presents alterations in the development of neurons and their connections, and result in an imbalance between the different types of electric signals in a range of brain regions. This is a result of alterations in the function of many genes, that are likely to be under the direct or indirect control of MECP2.

Sonia Guil
SAB Member

What research is being done?

A growing number of new experimental models in Rett syndrome has emerged in the last decade, and the combination of animal models with novel human systems based in the stem cell technology is boosting research in all areas. The field is evolving rapidly to include not only traditional cell culture systems but also three dimensional brain organoid models that recapitulate human neurodevelopment. With many different models and tools at hand, one primary goal is still to gain mechanistic insights as to the detailed function of MECP2 in regulating neuronal programmes. As basic research progresses, the global metabolic consequences of the loss of MECP2 function are better understood now, and allow an improved design of drug testing platforms to accelerate the transfer from preclinical to clinical assays. However, many of the therapeutic strategies currently in clinical assays target key deficits but not the original cause, and another important focus of research is the improvement of ways to deliver MECP2 and restore its normal levels in the damaged cells without toxic side effects.

Sonia Guil
SAB Member

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