1. What causes Rett syndrome (RTT)?

Rett syndrome is primarily caused by a sporadic mutation in the MeCP2gene on the X chromosome. A mutation is a change in the gene which results in abnormal function of the gene. The MeCP2 gene makes a protein, also known as MeCP2 which is important in regulating the activity of other genes responsible for the development and maturation of the brain and its connections (synapses). A change in the MeCP2 gene causes the failure of the regulatory mechanism resulting in other genes to function abnormally. This leads to disruption during the early dynamic phase of brain development, mostly at the end of pregnancy or in the first few months of life during the critical phases of synapse development. How exactly the change in MeCP2 gene leads to RTT syndrome is not well understood but is currently being researched widely.

2. Why is it called Rett syndrome?

Rett syndrome was named after Dr. Andreas Rett, who first recognized and described this syndrome. A syndrome is a group of symptoms - when put together these symptoms identify a special condition or syndrome. Girls with Rett syndrome show similar symptoms which were grouped together by Dr. Rett as "Rett syndrome".

3. What are the signs and symptoms of Rett syndrome?

The age of onset when the initial symptoms of RTT are noted may vary. In addition, the severity or intensity of symptoms also varies. The child with RTT is usually born healthy and shows an early period of apparently normal or near normal development until 6-18 months of life. This is followed by a delay in development or loss of skills (regression), mainly motor and language skills. Your child loses communication skills and purposeful use of her hands. In addition, there is slowing in the rate of head growth, resulting in small head size. Soon follow the stereotypical repetitive hand movements and gait disturbances. Other problems that may develop include seizures and disorganized breathing patterns during wakefulness. Your child may experience periods of isolation or withdrawal and irritability when she cries inconsolably. Over time, motor problems may increase, while interaction and communication, especially with eye gaze, seizures, and irregular breathing may improve.

4. My child has Rett syndrome. How will this affect our daily life?

Most girls with RTT require maximum supervision and assistance with almost all basic activities of daily living, such as eating, dressing, toileting, etc. You may have to lift and carry her, or help her walk, reposition her often for comfort, or change a bib for drool. You may have to program and reprogram a communication device. You need to learn how to keep them busy and entertained and at the same time teach them basic life skills. Entertainment devices such as a DVD or MP3 player, iPod or iPad are really helpful. You must know how to operate and keep these charged at all times. You need to learn how to find the right medical professionals and special equipment to help your daughter, schedule appointments and therapies and search for the right schools or programs. We need to take a really hard look at how we’re doing things and how it affects us and the rest of our family. While we can’t erase RTT today, we can face it. It is important to do all that we can, but at the same time recognize that we can’t do it all. We can learn from the information offered by the IRSF, collected over the years from thousands of parents, caregivers, and professionals, so we can make important changes that will make a positive difference in our daily lives.

5. How can I be sure my daughter has Rett syndrome?

Most parents know their daughters better than anyone. Often, they know that their daughter fits the Rett syndrome diagnostic criteria. In making this clinical diagnosis, specialists rely on a RTT Diagnostic Criteria Worksheet, which has been developed by the world's foremost authorities in RTT. Your child's doctor will look carefully at her early growth and development and will evaluate her medical history and physical and neurological status. Finding a MECP2 mutation is not necessary. However, most physicians use a blood test to confirm an abnormality in the MECP2 gene. This confirms the diagnosis for you. Based on the clinical features, your daughter may fall into one of two categories:
Typical or Classic RTT: those who meet the consensus diagnostic criteria;
Atypical RTT: those who do not meet all of the diagnostic criteria for classical RTT. The diagnosis of atypical RTT must include at least three of the primary criteria and five of the eleven supportive criteria. Atypical RTT accounts for 15-20 percent of all RTT diagnoses.
Types of atypical RTT include: Congenital Onset RTT: developmental delay is noticed shortly after birth with no early normal development; or severe seizures in early infancy impairing early development.
Late Onset RTT: signs are delayed beyond the typical 18 month onset, in some cases to age 10 years or more.
Preserved Speech RTT: milder features are seen
Male RTT: May be seen in males with Klinefelter (XXY) or somatic mosaicism.

6. What does my child’s mutation mean?

After the discovery of the MeCP2 gene, the diagnosis of RTT syndrome is made possible by a blood test. More than 200 different mutations in MeCP2 that cause RTT have been identified. However, eight specific mutations are the most common and account for more than half of all individuals with RTT. Most mutations are found in exons 3 and 4 (MeCP2 has 4 exons). Since 2004 a small number of mutations have been identified in exon 1. Even more importantly, the presence of large deletions was detected which consists of loss of an entire exon or more.
The diagnosis of the disorder, however, is still based on symptoms and clinical history. At this time, approximately 80 - 85% of all patients fulfilling the consensus criteria for RTT test positive for a MeCP2 mutation. This does not mean that the remaining 15% do not have RTT. Although testing positive for a mutation confirms the diagnosis it is not required. It is possible that mutations exist in an area of MeCP2 that has not yet been sequenced, or perhaps other genes contribute to RTT.

Combining this new information, 95% or more of girls fulfilling consensus criteria have mutations in MeCP2. In addition, we are now beginning to identify MeCP2mutations in males, some of whom have features of RTT, others lacking these features, but instead having much more severe problems leading to early death.

If a child is tested negative for MeCP2 mutations, testing for mutations that cause atypical RTT syndrome should be considered and are described as below.

Mutations in another gene on the X-chromosome known as CDKL5 (cyclin-dependent kinase-like 5) can cause an atypical form of Rett Syndrome called the early-onset seizure variant. These individuals test negative for a MeCP2 mutation. Not everyone with a CDKL5 mutation appears as atypical RTT. Other CDKL5 disorders include Infantile Spasms, West Syndrome, Early Onset Seizures, and Autism. CDKL5 mutation testing is not routinely available through most diagnostic labs. If you think your child should have this testing, you should discuss it further with your pediatrician, neurologist, or geneticist. For more information visit www.cdkl5.com">

Mutations on chromosome 14 on the gene FOXG1 can also be responsible for a congenital variant of Rett syndrome and generally test negative for a MeCP2mutation. Not everyone with a FOXG1 mutation appears as atypical Rett syndrome. For more information, visit fox1.com

Mutations in another gene on the X-chromosome known as WDR45, has recently been found in a few girls who have a clinical diagnosis of Rett syndrome and were not positive for MeCP2mutation.

7. My child development seemed so normal. What happened?

The change in MeCP2 results in a shortage or absence of normal MeCP2 protein needed to regulate or direct other genes that affect or control the normal development of selected regions of the brain responsible for sensory, emotional, motor and autonomic function during the critical period of infancy when important milestones are expected to be achieved.

8. Does my child’s mutation type determine her clinical features or symptoms (phenotype)?

Just as in any other disorder, the level of disability ranges from mild to severe. It is difficult to predict the intensity of symptoms in any individual child. Many girls begin walking within the normal range, while others show significant delay or inability to walk independently. Some begin walking and lose this skill, while others continue to walk throughout life. Still others do not walk until late childhood or adolescence. The same range holds true for using her hands and other skills she may acquire.

9. If it is genetic, does this mean I may have another child with RTT? Should family members be tested?

The chance of having more than one child with RTT is very small, much less than one percent. This means that more than 99.5% of the time, the mutation is sporadic, occurs only with this conception and is not repeated in a family. Overall, the bottom line on recurrence risks: If you have an affected daughter and no other affected relatives, the recurrence risk is much less than 1% for your family (you and your children). In families with more than one affected child, the situation is different and would need to be addressed individually through a skilled genetic counselor. Both parents can be tested for the mutation before deciding to have other children. If a mother has the mutation, then her daughters who seem to be unaffected may wish to be tested when they reach reproductive age as they too may be asymptomatic or silent carriers. Finally, prenatal testing of any babies conceived in a family where RTT has already occurred is also an option. These options all need to be explored individually through a skilled genetic counselor.

10. What kind of handicaps will she have?

Apraxia (dyspraxia), the inability (or reduced ability) to program the body to perform motor movements, is the most fundamental and severely handicapping aspect of RTT. It can interfere with every body movement, including eye gaze and speech, making it difficult for the girl with RTT to do what she wants to do. Due to this apraxia and her inability to speak, it is very difficult to make an accurate assessment of her intelligence. Most traditional testing methods require her to use her hands and/or speech, which may be impossible for the girl with RTT. Her mobility may be delayed and she may have difficulty crawling or walking.

11. Since skills are lost, is RTT degenerative?

Rett syndrome is not a degenerative disorder, but rather is a neurodevelopmental disorder. Barring illness or complications, survival into adulthood is expected.

12. How often does RTT occur?

The worldwide prevalence rate ranges from 1:10,000 to 1:23,000 live female births, making it two to three times more common in females than phenylketonuria (PKU), a congenital error of metabolism for which every newborn in the USA is tested. RTT is most often misdiagnosed as autism, cerebral palsy or non-specific developmental delay. While many health professionals may not be familiar with RTT, it is a relatively frequent cause of delayed development in girls.

13. What disorders must be ruled out?

Other possible conditions which could look like RTT must be ruled out. They include Angelman syndrome and the infantile form of neuronal ceroid lipofuscinosis. Females with RTT are often misdiagnosed as autism and cerebral palsy. Careful clinical assessment can differentiate these disorders.

14. How does RTT differ from autism?

The MeCP2 gene mutation is most often found in RTT. Some females with such mutations may exhibit features more typically seen in autism. While RTT occurs primarily in girls, autism occurs much more frequently in boys. In both conditions, speech and emotional contact are impaired. However, females meeting criteria for RTT do not meet those for autism and symptoms seen in RTT and not in autism include deceleration of the rate of head growth, loss of purposeful hand skills, and mobility or the irregular breathing patterns. While hand flapping is seen frequently in autism, the purposeless hand stereotypies that are common to RTT are not seen in autism. The girl with RTT almost always prefers people to objects, but the opposite is seen in autism. Unlike those with autism, the RTT girl often enjoys affection. While girls with RTT often have autistic-like features at an early age, these features disappear.

15. Is Rett syndrome seen predominantly in one race?

No. It affects all races and ethnicities.

16. What are the stages of Rett syndrome?

Stage I - Early Onset Stage Age: 6 months to 1.5 years Duration: Months
StageII - Rapid Destructive Stage Age: 1 to 4 years Duration: Weeks to Months
Stage III - Plateau Stage Age: Preschool to adulthood Duration: Decades
Stage IV - Late Motor Deterioration Stage Age: When ambulation is lost (those who never ambulate move from Stage II to IV, 5-25+ years Duration: Up to decades

17. Do all girls move through the stages of Rett syndrome similarly?

Not necessarily. The stages of Rett syndrome are guidelines provided to help understand the natural history of the disorder. The course of RTT is predetermined according to her mutation and X-inactivation status, and varies from one child to another, including the age when RTT begins and the speed and severity of symptoms. Therefore, two girls of the same age can appear quite different.

18. What will she be able to do?

Although the girl with RTT will need help for most activities of daily living, she can learn some independent skills. Girls can learn to use the toilet with assistance and may learn to feed themselves by hand or with utensils with some assistance. Some girls can learn to use augmentative devices to communicate. Despite their difficulties, girls and women with RTT can continue to learn and enjoy family and friends well into middle age and beyond. They express a full range of emotions and show their engaging personalities as they take part in social, educational and recreational activities at home and in the community.

19. What is my child’s life expectancy?

Due to the rarity of RTT, very little is known about long term prognosis and life expectancy. Most of those who have been identified are under 18 years of age. It is often difficult to identify older girls and women due to the frequent lack of complete infant and childhood developmental records. However, studies have determined that a girl with RTT has a 95% chance of surviving to age 20-25 years. This compares to a 98% survival probability for the general U.S. female population. Between the ages of 25-40, the survival rate drops to 69% in RTT, compared to 97% in the general U.S. female population. The average life expectancy of a girl given the diagnosis of RTT may exceed 47 years. While a few women in their 40's and 50's are known to have RTT, but too few women have been identified to make reliable estimates beyond age 40. While these statistics show that life expectancy is less in RTT, it is not nearly as low as previously thought or as other similar neurological disorders.

20. What are the causes of death?

It is important to note that only ~5% of cases reported to the IRSF have resulted in death. This means that 95% of those diagnosed are still living. The most frequently reported causes of death (one-quarter of deaths) are variations of sudden unexplained death with no apparent underlying cause such as an acute injury or infection. The factors most strongly associated with an increased risk of sudden unexplained death in RTT are uncontrolled seizures, swallowing difficulties and lack of mobility. Physical, occupational therapy, nutritional status or living arrangements made no difference in the incidence of sudden unexplained death. Other deaths have resulted from pneumonia. The factors most strongly associated with an increased risk of death by pneumonia are compromised lung function due to scoliosis and difficulty swallowing. Other causes of death include malnutrition, intestinal perforation or twisted bowel, as well as accidents and illness.

21. When she dies, what can we do to help find answers?

Although she may be at higher risk for life-threatening events such as pneumonia, choking and seizures, it is very likely that your daughter will live a long life. However, we are all at risk for accidents of many types and illnesses that are unexpected. A time will come when we will all die. Researchers are ready to listen, to learn, and to share. You can participate in research studies that will help us understand RTT.

22. What has research found?

Rett Syndrome was previously described as a neurodegenerative disorder, with very poor prognosis and little potential for learning. Scientific studies have now identified Rett Syndrome as a disorder of neurodevelopmental arrest, which begins shortly before or after birth at a critical time of brain and synapse formation.

23. What happens when she hyperventilates?

Deep breathing expels more carbon dioxide from the body than usual, so her hyperventilation causes her carbon dioxide level to fall. Carbon dioxide is one of the body’s normal waste products carried in the blood. Its purpose is to maintain the acid/alkali balance so that cells can function normally. When her carbon dioxide level falls, cells cannot function normally. Hyperventilation may cause her to feel dizzy and her fingers to tingle.

24. What happens when she holds her breath?

When she holds her breath, her oxygen level in the bloodstream falls. This may cause her to feel faint.

25. Are the abnormal breathing episodes or tremors related to seizures? Will she always breathe this way?

The abnormal breathing episodes can resemble epileptic seizures, but usually these are not seizures. Sometimes, what is thought to be a seizure is not, and some seizures may fail to be recognized when she is asleep or even awake. Vacant spells are brief interruptions of awareness that may resemble seizures. For the majority of girls, irregular breathing patterns become less noticeable as they get older.

26. What should we do about her irregular breathing?

Although episodes of breath holding produce great anxiety for parents to watch, they are always followed by regular breathing. Observing the irregular breathing can cause great concern, but experts in RTT recommend a low key approach, taking comfort in the fact that girls do become accustomed to the irregular breathing and regular breathing will soon return. While it may seem like forever, it is important to stay calm and in control.

27. How can breathing be so abnormal when she is awake and normal when she sleeps?

In Rett syndrome, irregular breathing typically occurs when she is awake and does not usually occur during sleep. During awake state, the periods of abnormal breathing result from probable immaturity of neurons regulating voluntary control of breathing mechanisms. During periods of sleep, automatic breathing systems prevail allowing her to breathe regularly and continuously. When abnormal breathing is seen in some girls with RTT during sleep, it is of the obstructive type, usually from enlarged adenoid/tonsils. Airway obstruction may be caused by mechanical problems in the breathing passages. Mouth breathing, snoring and frequent ear infections may signal that your daughter should be evaluated by an ear, nose, and throat specialist.

28. Are the breathing problems dangerous to her health?

They can be alarming to watch, and may make her somewhat uncomfortable, but they are not felt to cause permanent damage. Cessation of breathing during sleep is not typically seen in RTT. However, if your child stops breathing for short periods of time while asleep, you should talk with her physician. She may need testing to rule out airway obstruction. This is a separate problem from RTT, for which there is treatment.

29. How can I tell if she is swallowing air and if she is what should I do?

Air swallowing can be difficult to detect or may be prominently associated with breath holding. Air can be swallowed inadvertently in significant amounts each time she eats. It can also occur throughout the day in small amounts. If her upper abdomen is distended shortly after she eats it could be that she is swallowing air. If you suspect that she is swallowing air, there are a few things you can do. Decrease the length of mealtimes if it appears she is swallowing air while eating. Minimize stress and discomfort. Sit her in an upright position after she eats to help her burp and decrease the amount of gas in the stomach that is passed into the bowel. Keep on top of constipation so that gas does not accumulate in the mid intestine. If these measures are not adequate and her abdominal distention is severe, you may need to ask the advice of her physician on more aggressive methods.

30. Should she have an electrocardiogram (ECG)?

Yes. Some ECG abnormalities such as prolog QT interval is reported in children with Rett syndrome. By age 5, your daughter should have an ECG performed. If normal, it should be repeated every other year. If irregularities are noted on the electrocardiogram,, a cardiologist expert in electrical function of heart should be consulted. Nonspecific ECG changes probably do not warrant medications, but prolonged QT syndrome may require attention.