Ontario RETT SYNDROME Association

What is Rett syndrome?

Rett Syndrome (RS) is a unique developmental disorder which begins to show its affects in infancy or early childhood. It is seen almost exclusively in girls, although it can occur rarely in boys. It is found in a variety of racial and ethnic groups throughout the world.

What causes Rett syndrome?
 
Rett syndrome is caused by a mutation on the MECP2 gene of the X chromosome. The MECP2 gene is responsible for turning off other genes when they are no longer needed in development. (Most genes are active for only a specific period in development and then shut off forever.) The MECP2 mutation (change in the gene) causes the turn-off mechanism to fail, allowing other genes to stay active when they are no longer needed, and allowing proteins and enzymes to build up and become toxic to the central nervous system. So, RS is a genetic disorder of developmental arrest or failure of brain maturation. This is thought to occur when subsets of neurons and their connections (synapses) are disrupted during a very dynamic phase of brain development. This deviation occurs in the first few months of life, when synapses are normally being overproduced, only to be pruned later on to the normal adult number. In RS, these synapses appear to be under produced, or possibly over pruned.

She seemed to develop so normally. What happened?

RS results from a chain of events beginning with the MECP2 genetic mutation. Mutations occur naturally in everyone all the time and most do not cause problems. The MECP2 mutation results in a shortage or absence of MeCP2 protein needed to direct other genes. These downstream genes produce proteins or factors which control the normal development of selected regions of the brain responsible for sensory, emotional, motor and autonomic function. Development appears to be normal in early infancy until the factors are needed to be active or inactive, for further brain development. Without these factors, selected regions of the brain remain developmentally immature. This explains why the child appears to be developing normally in the first months of life.

If it is a genetic, does this mean I may have another child with RS?

The chance of having more than one child with RS is very small, less than one percent. This means that more than 99% of the time, the mutation is sporadic, just occurs on its own and is not repeated in a family

At what age does Rett syndrome begin?

The age when RS begins and the severity of different symptoms may vary. The child with RS is usually
born healthy and shows an early period of apparently normal or near normal development until 6-18 months
of life, when there is a slowing down or stagnation of skills. A period of regression then follows when she
loses communication skills and purposeful use of her hands. Soon, stereotyped hand movements,
gait disturbances, and slowing of the normal rate of head growth become apparent. Other problems
may include seizures and disorganized breathing patterns which occur when she is awake. There may
be a period of isolation or withdrawal when she is irritable and cries inconsolably. Over time, motor problems
may increase, while other symptoms may decrease or improve.

Since she loses skills, is RS degenerative?

Rett syndrome is not a degenerative disorder, but it is a developmental disorder. Barring illness
or complications, survival into adulthood is expected.
 
Apraxia Information

What kind of handicaps will she have?

Apraxia (dyspraxia), the inability to program the body to perform motor movements, is
the most fundamental and severely handicapping aspect of RS. It can interfere with every
body movement, including eye gaze and speech, making it difficult for the girl with RS 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 RS. Her mobility may be delayed
and she may have difficulty crawling or walking.
 
General Genetic Information

If it is a genetic, does this mean I may have another child with RS?

The chance of having more than one child with RS is very small, less than one percent.
This means that more than 99% of the time, the mutation is sporadic, just occurs on its own and is
not repeated in a family

How often does RS occur?

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

How is Rett syndrome diagnosed?

The diagnosis of RS is made on the basis of the presence of the MECP2 mutation (a blood test) and fulfilment of the diagnostic criteria. Most mutations are sporadic, and occur only once in a family. There are more than 100 mutations in the MECP2 gene which cause RS. Most of these are found in eight hotspots in the coding region of the gene (part of the gene which makes the MeCP2 protein). Mutations have been found in more than 80% of girls who fulfil the diagnostic criteria for RS. For the remaining 20% who do not currently show a MECP2 mutation, yet do still fulfil the diagnostic criteria, it is felt that their mutations are located in a part of the very large MECP2 gene not yet screened. So, at this time, it is possible to have RS with or without the MECP2 mutation. Because researchers now understand that the MECP2 mutation also causes other disorders, it is possible to have the MECP2 gene mutation and not have RS

What disorders must be ruled out?

Other possible conditions which could look like RS must be ruled out. They include Angelman syndrome (Happy Puppet Syndrome) and Prader-Willi syndrome, metabolic disorders such as OCT deficiency, disorders of organic acids and amino acids; storage diseases, mitochondrial disorders, and Batten Disease. While there are no scientific tests for them, autism and cerebral palsy are often misdiagnosed.

How does RS differ from autism?

The MECP2 gene mutation is found in RS and has also been revealed in some cases of autism, so they are branches of the same tree. While RS occurs primarily in girls, autism occurs much more frequently in boys. In both conditions, there is loss of speech and emotional contact. However, symptoms seen in RS and not in autism include deceleration of the rate of head growth and loss of purposeful hand skills and mobility. While hand flapping is seen frequently in autism as visual stimulation, the wider range of compulsive purposeless hand stereotypes common to RS are not seen in autism. The girl with RS almost always prefers people to objects, but the opposite is seen in autism. Unlike those with autism, the RS girl often enjoys affection. While girls with RS often have autistic tendencies at an early age, these features decrease over time.

What are the diagnostic criteria for Rett syndrome?

Most parents know their daughters better than anyone. Often, they know that Rett syndrome fits from the first description. Physicians use Diagnostic Criteria Guidelines
 
Stages and Severity of Rett Syndrome

What are the stages of Rett syndrome?

Stage I Early Onset Stage Age: 6 months to 1.5 years Duration: Months
Stage II Rapid Destructive Stage Age: 1 to 4 years  Duration: Weeks to Months
Stage III Plateau Stage Age: Preschool to school years Duration: Years
Stage IV Late Motor Deterioration Stage Age: When stage III ceases, 5-25+ years Duration: Up to decades

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

No. The stages of Rett syndrome are simply provided to help understand the natural history of the disorder. The course of RS is predetermined according to her mutation and X-inactivation status, and varies from one child to another, including the age when RS begins and the speed and severity of symptoms. Therefore, two girls of the same age can appear quite different.

Can the severity be predicted?

Just as in any other disorder, there can be a wide range of disability ranging 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

What will she be able to do?

Although the girl with RS will need help for most activities of daily living, she can learn some independent skills. Most girls can learn to use the toilet and many can 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 RS can continue to learn and enjoy family and friends well into middle age and beyond. They experience 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
 
Life Expectancy

What is life expectancy?

Due to the rarity of RS, 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 RS 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 RS, compared to 97% in the general U.S. female population. The average life expectancy of a girl given the diagnosis of RS may exceed 47 years. While there are a few women in their 40''s and 50''s who have RS, there have been too few women studied to make reliable estimates beyond age 40. While these statistics show that life expectancy is less in RS, it is not nearly as low as other similar neurological disorders.

What are the causes of death?

It is important to note that only 7% of cases reported to the IRSA have resulted in death. This means that 93% 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 RS are uncontrolled seizures, swallowing difficulties and lack of mobility. Neither physical or occupational therapy, nutritional status or living arrangements made a difference in the incidence of sudden unexplained death. Ongoing studies will help predict which girls are at greatest risk and which girls might benefit most from new medical or educational interventions. 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.

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 RS
 
Research Support

What has research taught us about RS?

Studies have revealed that although the brain is 30% smaller than normal, there are no obvious malformations, gross abnormalities or signs of infection. There is increased neuronal cell packing density. That is, cells should be further apart, but in RS they are very close together because cell-to-cell connections are not well-developed along the route. Neurons are reduced in size and there is reduced branching, which interferes with functions such as thinking, doing, and feeling. The number of synapses (brain-cell to brain-cell connections) is about half the normal number. Abnormalities in multiple areas of the brain may account for the following clinical symptoms:
Frontal lobe: Cerebral blood flow appears reduced, particularly in frontal brain regions. This looks like what might be seen in a 7 week-old child. This area is much more involved than other brain parts. It is necessary for mood and emotion
Caudate: much smaller than normal; involved in cognition, awareness and behaviour
Putamen: no anatomical change; necessary for movement
Temporal lobe (limbic system): no anatomical change; needed for memory, learning, emotion, behavior.
Cerebellum: reduction in some cell populations; needed for equilibrium and balance.
Hippocampus: no anatomical change; necessary for information processing.
Substantia Nigra: marked reduction in the pigment, melanin, and degeneration of cells; necessary for movement and critical thinking
Medulla (Brain stem): strong evidence of brain stem immaturity, leading to problems with the autonomic nervous system, such as sleep, salivation, breathing, heart rate, swallowing, bowel motility, blood circulation in hands and feet, and reduced sensitivity to pain.
Neurotransmitters: reduced. These include:
Dopamine - necessary for movement and critical thinking,
Acetylcholine - necessary for memory, cognition, movement control,
Glutamate - necessary for brain plasticity, important in seizures and cell death

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 developmental arrest, which begins shortly before or after birth at a critical time of brain and synapse formation.

How do we know that RS is a condition of developmental arrest?

Supportive Clinical Evidence
Early onset
Normal head size at birth
Low muscle tone
Weak cry and poor suck
Abnormal 4th toe (short)
Improved learning and gaining new skills
Supportive Neurobiological Evidence
Small brain
No malformations, storage, demyelinization, infection or gliosis
Dendritic arborizations, cell differentiation and neuronal growth affected
Small neurons with increased neuronal packing, migration not affected
Thinning of hippocampus
Significant involvement of caudate nucleus
Decreased melanin (pigment) in substantia nigra
Lack of mature olfactory (smell) neurons
Supportive Immunochemical Evidence
Early cholinergic deficits result in dendritic differentiation
MAP 2 decreased or absent in inner layer of cortex

These studies reverse the previous hypothesis of brain degeneration, opening doors to educational programs and therapies that will help. Studies have raised speculation that the primary conduction abnormality may be influenced by neurotrophic (growth) factors responsible for maturation of the heart and central nervous system. It is felt that these same neurotrophic factors may drive changes in the intestinal tract. These studies pave the way for treatments that will ultimately lead to a better way of life for girls with rett syndrome and a method to prevent sudden, unexplained deaths.
 
Breathing Concerns

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.

Are the abnormal breathing episodes or tremors related to seizures?

The abnormal breathing episodes can resemble epileptic seizures, but they are not. 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 but are not.

Will she always breathe this way?

For the majority of girls, irregular breathing patterns become less noticeable as they get older. The younger girl with RS appears to have more hyperventilation while the older girl has more of a type of breathing known as Valsalva’s maneuver.

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 RS 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. There is a lot of research at present directed at answering these questions.

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

In Rett syndrome, irregular breathing occurs only when she is awake and does not usually occur during sleep. When she is awake, the periods of abnormal breathing result from probable immaturity of neurons regulating breathing mechanisms. During periods of sleep, the changes in body function allow us to breathe regularly and continuously. When abnormal breathing is seen in some girls with RS during sleep, it is of the obstructive type, usually from enlarged tonsils. Airway obstruction may be caused by mechanical problems in the breathing passages. Mouth breathing, snoring and frequent ear infections may be signals that your daughter has a problem which should be evaluated by an ear, nose, and throat specialist.

How can I tell if she is swallowing air?

Air swallowing can be difficult to detect. Air can be swallowed inadvertently in significant amounts each time she eats. It can also occur throughout the day in small amounts. Sometimes it is easy to hear air as it is being swallowed. If her upper abdomen is distended shortly after she eats it could be that she is swallowing air. Here are some signs and symptoms associated with air swallowing:      
Audible swallowing at any time, including sleep
Severe dysfunction of swallowing with air swallowing apparent during eating or drinking
Abdominal distention, usually following feedings or episodes of hyperventilation and breath holding
Frequent burping (may be beneficial
Large amounts of gas passed through the rectum
If a large amount of air stays temporarily in the stomach, it will lead to sudden distention of the upper part of the abdomen. The stomach stretches, creating significant tension. If the girl with RS is unable to burp or pass gas, the bowel wall may become thin over time. This is especially true in individuals who have a poor nutritional status
Extreme distention of the wall of the stomach may lead to rupture. Several cases of gastric rupture have been reported in girls with RS. Once the stomach or any part of the intestine is torn, this will lead to peritonitis, an acute inflammation and infection of the abdominal cavity. Without immediate attention, peritonitis may lead to death. However, severe problems are infrequent, even though gastrointestinal problems are common in RS.
If air is passed into the intestine adequately, gastric distention will be less of a problem. But it can accumulate in the mid-intestine, causing distention of the abdomen and uncomfortable cramps. Constipation and medications that slow down the passage of stool can worsen abdominal
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. In some situations, even the frequent use of enemas (not routinely recommended) may be preferred to severe episodes of abdominal distention
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. This might include the placement of a tube through her nose into the stomach (nasogastric tube) or the placement of a tube through the abdominal wall into the stomach (gastrostomy button). This will help to decompress the bowel and allow the gas to flow out. It will prevent gas from advancing into the intestine. However, once the air is beyond the stomach, the bowel cannot be decompressed with any of these tubes. Some surgical interventions to prevent reflux, such as the Nissen fundoplication, in which the opening from the esophagus to the stomach is closed, may help in GE reflux, preventing heartburn or intermittent vomiting. At the same time, they can also increase the chances of a complication from air swallowing, since she is now unable to burp to get rid of gas
The risks and benefits of such surgery should be weighed carefully in each patient prior to making this decision. In rare situations, the placement of a colostomy (opening the bowel into the abdominal wall) may help in allowing adequate flow of intestinal contents and decrease the complications from inadequate passage of stool
Early detection as well as consultation with a gastroenterologist are extremely important to avoid progression of the problem and to manage it as early as possible, thus preventing more severe complications
 
Cardio Concerns

Should she have an electrocardiogram (ECG)?

As your daughter enters adolescence, you may wish to have an ECG performed.

What can be done about heart irregularities?

If irregularities are noted on the electrocardiogram, a cardiologist may be consulted. Nonspecific ECG changes probably do not warrant medications