| Frequently Asked Questions | |
Rett syndrome is a unique developmental disorder which begins to show its effects in infancy or early childhood. It is seen almost exclusively in girls, although it can occur rarely in boys. It is found in all racial and ethnic groups throughout the world. Rett syndrome is caused by a mutation in the MECP2 gene on the X chromosome. The MECP2 gene is responsible for turning other genes off and on (some genes are active for only a specific period in development and then shut off forever.) MECP2 mutations (change in the gene) cause the turn-on-off mechanism to fail, allowing other genes to stay active when they are no longer needed, or not come on when they are needed. She seemed to develop so normally. Rett syndrome 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 special regions of the brain responsible for sensory, emotional, motor and autonomic function. Development appears to be normal in early infancy until these factors that are required for further brain development need to be active or inactive. 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 Rett? 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 Rett syndrome begins and the severity of different symptoms may vary. The child with Rett 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. (I might add a little more hope here) Around school age, interaction and attention tend to improve and other symptoms may decrease or improve although motor performance may slow. 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 Rett syndrome. It can interfere with every body movement, including eye gaze and speech, making it difficult for the girl with Rett 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. Her mobility may be delayed and she may have difficulty crawling or walking. Since she loses skills, is Rett syndrome degenerative? Rett syndrome is not a degenerative disorder, but it is a developmental disorder. Barring illness or complications, survival into adulthood is expected. How often does Rett syndrome occur? 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. The incidence rate is about 1:10,000 female births. However, Rett syndrome has most often been misdiagnosed as autism, cerebral palsy or non–specific developmental delay. How is Rett syndrome diagnosed? The diagnosis of Rett syndrome is made on the basis of the fulfillment of the diagnostic criteria. The presence of the MECP2 mutation (a blood test) confirms the diagnosis. Most mutations are sporadic, and occur only once in a family. There are more than 200 mutations in the MECP2 gene which contribute to Rett syndrome. 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 95% of girls who fulfill the diagnostic criteria for RS. For the remaining 5% who do not currently show a MECP2 mutation, yet do still fulfill 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 Rett syndrome 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 Rett syndrome. What disorders must be ruled out? Other possible conditions which could look like Rett syndrome must be ruled out. They include Angelman syndrome (would remove this; it is out of favor Happy Puppet Syndrome) and Prader–Willi syndrome (not too likely to confuse with RS), metabolic disorders of the urea cycles such as Ornithine transcarbamylase deficiency) deficiency and of organic acids and amino acids; storage diseases such as Batten disease, and mitochondrial disorders. While there are no scientific tests for them, autism and cerebral palsy are often misdiagnosed as Rett syndrome. How does Rett syndrome differ from autism? Mutations in the MECP2 gene are found in Rett syndrome and have also been identified in some girls with autism, so they are branches of the same tree. While Rett occurs primarily in girls, autism occurs much more frequently in boys. In both conditions, there is loss of speech and emotional contact. However, features seen in Rett 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, the wider range of compulsive purposeless hand stereotypies common to Rett are not seen in autism. The girl with Rett almost always prefers people to objects, but the opposite is seen in autism. Unlike those with autism, the girl with Rett syndrome often enjoys affection. While girls with Rett syndrome often have autistic tendencies at an early age, these features decrease over time. How is the Rett diagnosis made? The first step should be for your child’s doctor to look carefully at her early growth and development and evaluate her medical history and physical and neurological status. In making the diagnosis, specialists rely on a RS Diagnostic Criteria Worksheet, which has been developed by the world’s foremost authorities in Rett syndrome. After the clinical diagnosis is made or suspected, the next step is to get the MECP2 blood test. Your daughter may fall into one of three clinical categories:
Types of atypical RS include:
What are the diagnostic criteria for Rett syndrome? How can I be sure my daughter has it? Most parents know their daughters better than anyone. Often, they know that Rett syndrome fits from the first description. Physicians use the following Diagnostic Criteria Guidelines: Necessary criteria (must be present for the diagnosis)
Supportive criteria (not necessary for the diagnosis, but may also be seen)
Exclusion criteria (rule out the diagnosis)
Is Rett syndrome seen predominantly in one race? No. A statewide population study in Texas has revealed that the incidence of RS in the African–American and Hispanic population in the United States is comparable to that in Caucasian Americans. What are the stages of Rett syndrome? The stages for Rett syndrome were developed by Prof. Bengt Hagberg and colleagues prior to the identification of mutations in MECP2. At present, they are not widely used by physicians in this country.
For more information about the stages of Rett syndrome http://www.rettsyndrome.org/main/stages.htm 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 Rett syndrome is predetermined according to her mutation and X-inactivation status as well as other yet to be determined factors, and varies from one child to another, including the age when Rett 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 patterns hold true for using her hands and other skills she may acquire. Although the girl with Rett syndrome 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 Rett 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.
Due to the rarity of Rett syndrome, 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 Rett 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 Rett, compared to 97% in the general U.S. female population. The average life expectancy of a girl given the diagnosis of RS may exceed 50 years. New data from the IRSA-supported North American database indicate that 50% survival may extend beyond 50 years. (manuscript in preparation). While these statistics show that life expectancy is less in Rett, it is not nearly as low as other similar neurological disorders. 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 nor occupational therapy, nutritional status, and living arrangements made a difference in the incidence of sudden unexplained death. Ongoing studies should 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. Girls with Rett syndrome are as likely as any child to have the common pediatric disorders such as cystic fibrosis or diabetes mellitus. 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 and post-mortem examinations that will help us understand Rett syndrome. What has research taught us about RS? Studies have revealed that although the brain of an individual with Rett syndrome 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:
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
Supportive Neurobiological Evidence
Supportive Immunochemical Evidence
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. What are the clinical research findings in Rett syndrome? Autonomic Findings
Biochemical Findings
Cardiovascular Findings
Nutritional Findings
Neurophysiological Findings
Neuropathological Findings
The prevalence of Rett syndrome is 1 per 22,800 (0.44/10000) females aged 2–18 years of age as determined in the Texas Rett Syndrome Registry. Incidence values are limited, varying from 0.43-0.71/10,000 females in France to 1.09/10,000 females in Australia. Rett syndrome has been reported in all races and ethnic groups. Rett individuals have an estimated 70% survival at age 35 years; this contrasts sharply with an estimated 27% survival at 35 years for severely retarded individuals. The majority of deaths in Rett syndrome are either sudden and unexpected or secondary to pneumonia. |
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