Edited by Shane R. Jimerson, Ph.D.
Contributed to by the Graduate Students in the Counseling, Clinical, and School Psychology Program at the University of California, Santa Barbara.
Ongoing design and publication of this site is completed by Shane R. Jimerson, Jeff R. Klein and Angela D. Whipple. Please forward comments regarding this site to Shane R. Jimerson. This page was last updated 1.11.02. © 2002
Shane R. Jimerson, Mendy Boettcher, Catherine M. Brown, and Monette Tijerina
University of California, Santa Barbara
Rett syndrome was named for Dr. Andreas Rett,
after his original documentation of the symptoms in 1966. However, it
did not become internationally recognized until 1983 (Tsai, 1992). Presently,
Rett syndrome has only been documented in females, and as of 1995 there
were 2237 cases recognized around the globe, 1817 of which were in the
United States (Treffert, 1999). Rett syndrome is classified as a
severe developmental disorder usually diagnosed between six and twenty-four
months (Perry, Sarlo-McGarvey, & Haddad, 1991). Rett syndrome is psychophysiological
in nature, and impairs cognitive, socioemotional, and physical functioning
(Watson, Umansky, Marcy, Johnston, Repacholi, 1996). This syndrome is characterized
by apparently normal prenatal, perinatal, and early infancy development,
followed by decelerated head growth, loss of purposeful hand movements
(Volkmar and Lord, 1998), and rapid deterioration of physical and mental
capacities, resulting in severe to profound mental retardation (Tsai, 1992).
Due to some of the exhibited symptoms, such as stereotypical movements and social withdrawal, children with Rett syndrome are often initially diagnosed as having infantile autism (Tsai, 1992). This is particularly true during the preschool years, prior to the onset of the more advanced stages of Rett’s Syndrome, when many behaviors of children with autism and Rett’s are very similar (Volkmar and Lord, 1998). After the preschool years the progression of Rett’s becomes quite distinctive, therefore, it is less likely to be confused with autism after a certain point (Tsai, 1992). Other common behaviors seen in Rett’s patients include breath holding, air swallowing, motor problems (ataxia and apraxia), and stereotyped hand movements, such as hand wringing (Tsai, 1992).
Until October of 1999 the cause of Rett syndrome was largely unknown. A gene mutation has since been identified which is thought to be the cause of this syndrome (Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y., 1999; Schanen, 1999; Bienvenu, et al., 2000; Buyse, et al., 2000; Cheadle, et al., 2000; Meloni, et al., 2000), although the mechanisms by which it operates are not well understood. As research in this area is very new, there are still many discoveries to be made before this finding will have significant bearing on the lives of Rett patients and their families (International Rett Syndrome Association, 1999). Since Rett syndrome is still a relatively under researched disorder, there continues to be a need for further research in all areas, including etiology, progression, and intervention.
Return to Top
DSM-IV Criteria for 299.80 Rett’s Disorder (American Psychiatric Association, 2000)
A. All of the following:
1) apparently normal prenatal and perinatal development
2) apparently normal psychomotor development through the first 5 months after birth
3) normal head circumference at birth
B. Onset of all of the following after the period of normal development:
1) deceleration of head growth between the ages 5 and 48 months
2) loss of previously acquired purposeful hand skills between ages 5 and 30 months with the subsequent development of stereotyped hand movements (e.g., hand-wringing, or hand washing)
3) loss of social engagement early in the course (although often social interaction develops later)
4) appearance of poorly coordinated gait or trunk movements
5) severely impaired expressive and receptive language development with severe psychomotor retardation
SUPPORTIVE CRITERIA (not required for diagnosis, but commonly seen (Schilling, 1997)):
1) Breathing dysfunctions which include breath holding or apnea, hyperventilation
and air swallowing which may result in abdominal swelling
2) EEG abnormalities which include slowing of normal electrical patterns, the appearance of epileptiform patterns and a reduction in REM sleep
4) Muscle rigidity/spasticity/joint contractures
6) Teeth grinding (bruxism)
7) Small feet
ICD-10 Research Diagnostic Criteria (World Health Organization, 1993):
A. There is an apparently normal prenatal and perinatal period
and apparently normal psychomotor development through the first five months
and normal head circumference at birth.
B. There is a deceleration of head growth between five months and four years and loss of acquired purposeful hand skills between five and thirty months of age that is associated with concurrent communication dysfunction and impaired social interactions and the appearance of poorly coordinated/unstable gait and/or trunk movements.
C. There is severe impairment of expressive and receptive language, together with severe psychomotor retardation.
D. There are stereotyped midline hand movements (such as hand-wringing or “hand-washing”) with an onset at or after the time when purposeful hand movements are lost.
Return to Top
Although the established DSM-IV and ICD-10
criteria for Rett syndrome do not include “female sex” as a part of the
diagnosis there are currently no documented cases of males diagnosed with
the syndrome (Tsai, 1992). As it is now known that Rett syndrome
is caused by a sex linked gene mutation, researchers believe that this
mutation is fatal in males (Amir, et al., 1999; Meloni, et al., 2000).
So far only one male with this gene mutation has been reported; this individual
only survived to one year of age (Meloni, et al., 2000). The fatality
of this gene for male fetuses accounts for the fact that all documented
cases have occurred in females. Rett syndrome is believed to occur
in every 1 to 10,000-15,000 live births (Tsai, 1992; Glasson, et al., 1998;
Deb, 1998). This syndrome is believed to exist worldwide and among all
different races (Tsai, 1992). There are four stages of developmental
regression associated with Rett syndrome (Braithwaite, 1997). Stage 1 is
characterized by a decline in head growth rate. Stage 2 is marked
by the loss of previous language acquisition (if any), loss of purposeful
hand movements, lack of social interest, and other autistic-like behaviors.
Stage 3 includes stereotypical hand movements (“hand washing”, hand wringing,
hand clasping, and hand mouthing) and poor muscle control and coordination
(most notable in an awkward gait), yet social interactions tend to increase.
In stage 4, muscular coordination deteriorates further. Although individuals
with Rett syndrome survive into adulthood, they eventually become severely
mentally and physically incapacitated and require ongoing care throughout
their lives (Perry, et al., 1992). Most current research indicates
that there is limited significant treatment gains with this population
(Perry, et al., 1992).
Although there is now a genetic marker for Rett syndrome, diagnosis is still largely based on the presence or absence of certain behavioral and clinical criteria, such as deceleration of head growth, loss of skills, and emergence of stereotypic behaviors such as hand wringing (International Rett Syndrome Association, 1999; Glasson, et al., 1998; Mazzocco, Pulsifer, Fiumara, Cocuzza, Nigro, Incorpora, & Barone, 1998). While the gene has been discovered, the exploration of the various types of mutations on that gene that are responsible for Rett’s is still incomplete (International Rett Syndrome Association, 1999). This means that while tests can determine the presence or absence of mutated genes, there is still not enough known about the gene to use such tests as a diagnostic tool or screening device for Rett syndrome (International Rett Syndrome Association, 1999). This lack of a specific test for diagnosis leads to diagnostic challenges, such that children who develop this syndrome are often still misdiagnosed in their preschool years when their behaviors appear quite autistic like. The progression of this syndrome often takes years, therefore, it may be difficult to make a conclusive diagnosis until the child progresses through two or more stages of the disorder (Volkmar & Lord, 1998; Mazzocco, et al., 1998; Glasson, et al., 1998).
The gene which causes Rett’s has now been discovered, however, there are still other types of research taking place which may yield helpful phenomenological and diagnostic information. A recent study by Glasson et al. (1998) is a good example of this research. This study looked at radiographs of hands and feet from a group of girls diagnosed with Rett syndrome as compared to control radiographs from individuals with no diagnosis. Specifically, they measured the presence of relative shortening of the fourth metacarpal (finger) and fourth metatarsal (toe), as well as the presence of a short ulna (bone in the forearm). The body of research which lead to the hypotheses in the current study is discussed in this article. While the researchers did not find support for any of their hypotheses in children under five years of age, shortening of all three bones was found more often in individuals with a diagnosis of Rett’s than in those without the diagnosis in individuals over five years of age. There was some variation in the results based on age as well as which hand or foot (right versus left) was being examined. These variations are clearly explained in the article. The authors discuss the importance of their findings and their possible use in making a definite diagnosis of Rett syndrome. Perhaps the most relevant of their outcomes is their calculation that the frequency of a shortened fourth metacarpal in the right hand of individuals with Rett’s was more than twice that of controls. While more research is needed in this area, these findings may lead to important information which could alleviate some of the confusion in diagnosing Rett syndrome until the genetic marker can be used for this purpose. It is important to note, however, that as these physical differences do not appear to manifest prior to age five, this study does not provide any insight into the convoluted question of how to diagnose children prior to this age and how to differentiate them from children with autism. This study is also relevant to the study of epidemiology and phenomenology as the symptom these authors describe has not been conclusively documented to date. The authors suggest that the criteria derived from their study be added to the list of criteria which support a diagnosis of Rett syndrome, but are not part of the diagnostic criteria (Hagberg and Skjeldal, 1995).
Some researchers have proposed that Rett syndrome be broken down into subtypes of the disorder that would more specifically describe differences in behaviors, characteristics and symptomology (Zapella, Gillberg, & Ehlers, 1998). For example, Zapella, Gillberg, and Ehlers (1998) proposed that Rett syndrome is actually a spectrum of syndromes, ranging from severe cases that present with all the classic symptoms to milder variants. Specifically, the authors believe that they have identified a group of 30 girls who meet full criteria for autism and partial criteria for Rett syndrome, but whose speech abilities are preserved such that their symptoms are not characteristic of either diagnosis. They have named this subgroup the “preserved speech variant” and contend that these individuals do not have either autism or classic Rett syndrome, but that they have another separate syndrome which lies on a continuum of the Rett diagnosis. The article describes these 30 girls and provides a rationale for why the authors believe they should be diagnosed as having the preserved speech variant of Rett’s as opposed to the classic Rett syndrome diagnosis. The discussion contains a thorough description of the four stages of Rett syndrome seen in these girls, which are somewhat different than the four stages seen in the classic syndrome. As research in this area is still developing and is therefore inconclusive, individuals who are interested in the diagnosis of this possible subgroup of Rett syndrome are encouraged to monitor the research in this area as more literature is published and new resources are made available. The authors of this article state, “it is yet early to determine whether or not all these 30 female cases have a variant of Rett syndrome, autistic disorder, a combination of the two, or a ‘new’ disorder” (Zapella, Gillberg, & Ehlers, 1998; p. 524). Current genetic research may also yield important information that may explain the variance these authors describe. Specifically, it is now hypothesized that individuals with greater severity of symptoms may have a greater number of mutated genes expressed in their DNA than those with milder symptoms (International Rett Syndrome Association, 1999). This finding provides a possible physiological explanation for the phenomenon that these authors observed in their “preserved speech variant.”
Because Rett Syndrome is not well understood there is some debate about whether it should be considered a neurological or psychiatric disorder (Volkmar & Lord, 1998). Prior to the development of DSM-IV (American Psychiatric Association, 1994), a large field trial was undertaken to evaluate the diagnostic criteria of the disorders classified as pervasive developmental disorders (PDD; Volkmar et al., 1994). While the results of this trial primarily focused on the criteria for autism, they provided some support for the inclusion of Rett Syndrome in the PDD class in the DSM-IV (Volkmar & Lord, 1998). The primary reason for including this syndrome in the DSM-IV was to increase awareness of its criteria and reduce the number of incorrect autism diagnoses given to children with Rett Syndrome (Volkmar & Lord, 1998).
This debate has been, and remains somewhat controversial in the field, however. For example, Tsai (1992) provides an extensive discussion on whether Rett syndrome should be classified as a subtype of the pervasive developmental disorders or classified in its own category within the mental retardation domain. He also contends that consideration should be made for a classification of “atypical Rett syndrome” for those individuals who exhibit/possess most of the criteria but not all of them. The author highlights general characteristics and criteria that both include and exclude those characteristics considered for receiving the diagnosis, and compares characteristics associated with autism and Rett syndrome as these disorders are often mistaken for one another during the preschool years. In addition, the author debates whether Rett syndrome should be classified as a neurological disorder or a mental disorder. The author concludes that further research is necessary in the field of Rett syndrome. This debate is likely to be greatly influenced by the discovery of the gene that causes Rett’s, especially as more research findings are published in this area.
Many other behaviors and comorbid disorders may be seen in individuals with Rett syndrome, but are not considered diagnostic criteria. For example, it has been noted that approximately 50% of girls with Rett syndrome develop epilepsy (Deb, 1998). In addition, Deb (1998) also noted that over 70% of individuals with this disorder suffer from disturbed sleep. Other behavioral problems cited in the literature include, crying, screaming, teeth grinding, facial grimacing, and breath holding (Deb, 1998). Finally, Deb (1998) stated that self-injurious behavior, particularly damage to hands, has been seen in 39-49% of girls with Rett syndrome. While this author’s description of Rett syndrome in particular is somewhat brief, he describes upwards of ten other genetic syndromes (such as Prader-Willi, Lesch-Nyhan, and de-Lange syndrome) and notes some of the similarities and differences among them, especially with regard to self-injurious behavior.
There is also a growing body of literature on the communicative and cognitive abilities of girls with Rett syndrome. As these are important diagnostic criteria they warrant discussion when addressing difficulties of diagnosis. These areas will also be addressed in the discussion of assessment and intervention. One example of a study by Woodyatt and Ozanne (1992) focuses on the communicative and cognitive competence of 6 females (2-13 years old) with Rett syndrome. Three of the younger subjects were at the third developmental stage of Rett’s and the three older subjects were at the fourth developmental stage. Observation and videos were used to determine types of communication behavior. These behaviors included non-linguistic communication, such as eye gaze and touching. Interviews were also completed with parents and caregivers to confirm behavioral observations. For the cognitive assessment, the examiners used a modified version of the Uzgiris and Hunt Scales of Infant Psychological Development, which measures attention, reaching, gestures and vocal communication in relation to objects in the environment. This study found that children with Rett syndrome are not expected to make developmental gains in intentional communication. The researchers also concluded that this lack of communication may not be due to the lack of purposeful hand movements as much as it is to the lack of motivation to communicate. Researchers recommend functional assessment.
In another such study (Meyer, Kennedy, Shukla, & Cushing, 1999), the researchers conducted a receptive communication analysis for a female with late-stage Rett syndrome. Individuals in the participant’s life reported that she was communicating via eye blinks in spite of the fact that she was unable to vocalize or move her extremities. The authors tested this hypothesis using “communication trials” in which they would show her an object and then ask her to receptively indicate what she had seen. Based on the number of correct trials, the authors concluded that the individual was not communicating via eye blinks at a level which was greater than random chance. They report that their data suggest that “reports of her communication were based on inferences of those who had known Jane for a lengthy period of time” (Meyer, et al., 1999; p. 93). Finally, these authors state that they believe their results indicate that cognitive functioning in individuals with late-stage Rett syndrome is significantly impaired.
In summary, Rett syndrome is a unique and puzzling developmental disorder which only affects a small percentage of the population. This disorder may be particularly stressful for families given that normal development progresses for the first months of life, followed by a sudden regression with irreversible effects (Perry, Sarlo-McGarvey, & Factor, 1992). This severe developmental disorder affects not only cognitive and motor functioning, but also significantly impairs communication and social interactions (Perry, et al., 1992). As the genetic marker for Rett’s has just recently been discovered, diagnosis still presents some unique challenges and the disorder is often confused with autism early in a child’s life. There is current debate in the field about how and where Rett syndrome should be classified and whether it is a discrete syndrome or more of a spectrum of variations on the classic Rett’s diagnosis. In addition, current research is investigating more conclusive characteristics of this disorder which could possibly make diagnosis easier and more definite. Researchers are also discovering new information about the gene that causes Rett syndrome at a rapid rate. This type of information is likely to transform the areas of diagnostics, etiology, assessment, and possibly even intervention. More research is necessary for further understanding of this disorder in all areas.
Return to Top
The etiology of Rett Syndrome remains an enigma
in many ways, although much progress has occurred in recent years.
Initially, Dr. Andreas Rett suspected that the disorder was the result
of high peripheral ammonia levels (Van Acker, 1997), but this has never
been confirmed. Since there have only been confirmed cases of classic Rett's
in females, it has always been suspected that this syndrome is genetically
linked. Investigative efforts to identify this genetic link in the past
have come up with inconclusive evidence. Recent research has revealed
some new and important findings, however. Specifically, in 1999 mutations
on a specific gene, called MECP2, were identified which have been found
to be associated with Rett syndrome (Amir, et al., 1999). While much
about these mutations remains a mystery and further research is needed,
the original findings of Amir and colleagues (1999) have been replicated
and are currently accepted as fairly conclusive in the field (Schanen,
1999; Bienvenu, et al., 2000; Buyse, et al., 2000; Cheadle, et al., 2000;
Meloni, et al., 2000). That is, the field widely accepts that the
cause for Rett syndrome lies somehow in mutations which have been found
on the MECP2 gene, but these mutations and the mechanisms by which they
alter development are not yet understood.
There have been many hypotheses regarding the cause of Rett syndrome. One of the foremost hypothesis has been that Rett syndrome is an X-linked phenomena. Comings (1986) and Riccardi (1986) reported that this dominant X-linked gene might "cause early abortions of hemizygous male fetuses and a dominant phenotype in heterozygous females." In other words, this strong X-link factor may force male fetuses to spontaneously abort while coming into fruition in the female, thus creating a female who exhibits Rett Syndrome. This hypothesis has always been a possible explanation of why there are no confirmed cases of classic Rett's in males. Zoghbi (1988) suggests the possibility of a nonrandom X-chromosome inactivation in the mother of daughters with Rett's. However, a study by Anvret and Wahlstrom (1992) could not support this hypothesis, as none of the females in the family who participated in the study exhibited the specific nonrandom inactivation process used to explain Rett syndrome.
Many other theories emerged over the years in an attempt explain the genetic etiology of Rett syndrome. For example, Wahlstrom and Anvret (1986) developed a model to explain Rett's that differs from those discussed above. They proposed a two-step mutation in which girls with the syndrome inherited a mutated gene in one of their X-chromosomes, "in addition to a somatic mutation at the same locus in the other X-chromosome." This somatic cell or mutated gene in a male zygote would cause a premature abortion in utero. Buhler, Malik, and Alkan (1990) proposed yet another alternative hypothesis for the inheritance of Rett's. Their model "proposes the action of an autosomal modifying gene in addition to the X-chromosomal ‘Rett’ gene, which interferes with a locus on the X-chromosome." A female whose chromosome at the autosomal locus has mutated will simply be a carrier of the Rett Syndrome. However, if the chromosome does not mutate, then Rett's will develop. Others have proposed that translocations in the short arm of the X-chromosome may develop into Rett's, such as t(X;3) (Zoghbi, et al., 1990) and t(X;22) (Journel, et al., 1990). In addition, research has been conducted on the Fragile X sites since this disorder has been reported in a number of autistic syndromes. Although a couple of these sites have been explored, this theory has since been dropped as both sites can be found in phenotypically normal females (Barbi, et al., 1984; Sekul & Percy, 1992).
Building on this past research, recent studies have revealed new information which somewhat alters how the field is now approaching the genetics of this disorder. As Rett syndrome is know known to be genetically based (Amir, et al., 1999; Schanen, 1999; Buyse, et al., 2000; Meloni, et al., 2000), the search for its specific etiology has become significantly narrowed. While researchers still have a great deal to learn about genetics in this area, the evidence that a mutation on the MECP2 gene is somehow the cause for Rett syndrome has been replicated numerous times since the original publication in 1999 (Amir, et al., 1999; Bienvenu, et al., 2000; Buyse, et al., 2000; Cheadle, et al., 2000).
A recent study by Buyse, et al. (2000) examined a new method for testing for the presence or absence of the MECP2 gene mutation. The researchers feel this method may be a feasible test to use for diagnostic purposes. Specifically, they utilized a two-tiered process in which an initial screening was first performed, followed by a confirmatory analysis in which a more precise mechanism for verifying the presence of the mutation was used. The authors found MECP2 mutations in 84% of individuals previously diagnosed with classic Rett syndrome (based on the clinical criteria), and 40% of patients with a previous diagnosis of possible Rett’s. In their discussion of these findings, the authors conclude that “this two-tiered approach provides a sensitive, robust, and efficient strategy for RTT molecular diagnosis” (pp. 1435). In addition, they note that no current method has 100% detection under all conditions, and that because their method is less “labor and reagent intensive” than other methods, it may be the most desirable option available to date. They also note that this method is more cost effective than most other available methods.
The recent breakthroughs in genetic research on Rett syndrome have provided some new information which may alter the previous beliefs about the differences between males and females with this gene mutation. It was previously believed that males with the gene mutation that is responsible for Rett’s would spontaneously abort or die in utero, while females would survive to manifest the syndrome during their first few years of life (Comings, 1986; Riccardi, 1986; Wahlstrom & Anvret, 1986). Recent research has brought this theory into question as several cases have been discovered where males with a mutation on the MECP2 gene displayed symptoms which may be related to Rett syndrome (Wan, et al., 1999; Meloni, et al., 2000). Specifically, Meloni, et al. (2000) studied two related males with MECP2 mutations who showed severe mental retardation and progressive spasticity. The authors cited these symptoms as evidence that in males the MECP2 gene can be responsible for severe mental retardation associated with neurological disorders, as the unaffected males in the family did not carry the gene. Interestingly, two females in the same family were carriers of the gene, but did not manifest symptoms of Rett syndrome. They were of borderline and average intelligence, simulating an X-linked recessive trait. There are still many mechanisms about the MECP2 gene that are not well understood (Schanen, 1999). For example, it is unknown how this gene may be passed between family members, whether it may manifest as a result of a random mutation, and how some individuals with the gene do not develop the phenotype that has been associated with it. This study, in which two male carriers displayed significant abnormal development and two female carriers did not manifest Rett syndrome, may aid researchers in learning more about how the mutation is caused and the mechanisms by which it leads to abnormal development.
In a related study, Wan, et al. (1999) explored the spectrum of phenotypes resulting from MECP2 mutations. They identified several different types of mutations on this gene in individuals with varying phenotypes ranging from classic Rett syndrome to normal development. Specifically, some individuals with the gene had classic Rett syndrome, while others experienced difficulties, such as motor coordination problems and learning disabilities, without meeting criteria for classic Rett’s. The researchers hypothesize that the individuals with milder phenotypes have greater inactivation of the mutated genes (a normal part of development where some genes become inactivated and others are expressed) than those whose symptoms are more involved. They also found similar mutations in the son of an individual with the mutation, but he died very early on from congenital encephalopathy. Similar to the previously mentioned study, these authors conclude that some males with MECP2 mutations may survive to birth and females with favorably skewed X-inactivation patterns may have few or no Rett-like symptoms. The authors caution that MECP2 mutations are not limited to Rett syndrome and may be “implicated in a much broader phenotypic spectrum.” Other studies have noted that individuals with MECP2 mutations may have Rett-like symptoms without manifesting classic Rett syndrome (Kim & Cook, 2000). Further research in this area is still necessary before we will have a clear understanding of how MECP2 mutations are implicated in the underlying genetics of Rett syndrome.
There is a growing body of literature in this area, but research is still inconclusive regarding the manner in which the MECP2 gene mutation occurs and the mechanisms by which is causes abnormal development. In an article by Schanen (1999) the history of genetic research and theories in this area is outlined, culminating in a review of what we currently know, what we still do not understand, which theories have been disproved, and where researchers might focus their efforts in the future. Schanen hypothesizes that neurochemical and anatomic alterations indicate that Rett syndrome appears to result from an arrest of neuronal maturation. The author notes that the recently identified MECP2 mutations lie in the area that previous research was pointing to, but that the mechanisms by which this gene causes abnormal development have not been experimentally demonstrated. The author speculates that these mechanisms likely involve inappropriate expression of genes which would have been silenced had a mutation not occurred. These inappropriate expressions would then somehow lead to an arrest of normal neuronal maturation. Most important, however, is that more research in this area is needed before we can truly understand how the genetic etiology of Rett syndrome specifically works.
It may also be useful to examine the etiology of Rett syndrome from a developmental perspective. Developmental psychopathology looks at abnormal development over time as compared to normal development. It examines the source of the aberrant behavior, as well as the individual adaptation and success of the person. From a developmental perspective, there are generally two major contributors to each individual's development: genetics and environment. The development of Rett Syndrome could definitely encompass both. Although the recent finding of a biological marker is not yet well understood, it is now accepted that there is a genetic basis for this disorder, thus we know it begins developing in utero. It is still not well understood how the mutation comes to exist, and why some mutations are different than others, but still cause Rett syndrome (Schanen, 1999). The possibility of a teratogen invading the zygote and causing the mutation can still be considered. Hence, both biological and environmental factors may contribute to the development of Rett syndrome.
Although research in this area appears to be fairly sparce, some researchers believe that environmental factors after birth may also play a role in the development of Rett syndrome. For example, in an article by Fiumara, et al. (1999), the authors outline the progression of an individual’s Rett symptoms, which began in a dramatic manner after the patient experienced an infectious disease with a high fever accompanied by a seizure. Through photographs, the article attempts to demonstrate normal development through two years of age, followed by the rapid onset of Rett symptoms. The authors note that the child’s regression was rapid and onset of the syndrome was much quicker than normal. They conclude by suggesting that the onset of Rett syndrome can follow an infections disorder in genetically predisposed individuals, and that rapid onset is possible in such cases. Although this hypothesis does not appear to be widely accepted in the literature, it is a good example of how environment and genetics may be inexplicably intertwined and further research in this area is warranted.
Although development appears to be normal for the first six months of life, those afflicted with Rett Syndrome will soon exhibit signs of abnormal development, such as regression in behaviors, lack of social interest, and deceleration in head growth. Thus, it may appear that the child has contracted an illness, when in reality, she has always had it but now it is manifesting itself in abnormal behaviors and growth. The symptoms of Rett Syndrome become apparent within the first year of life. Therefore, from a developmental perspective, it cannot be surmised that a child will eventually contract Rett syndrome, but rather she is born with it. Research has shown that there is not much that can be done to alter the course of development of these children, but rather interventions/treatments can be conducted to possibly decrease some of the effects of further damage (e.g., medication to help minimize seizure activity).
Initially, Rett syndrome was characterized as a neurodegenerative disease, most likely due to the loss of skills and deceleration of head growth that are characteristic of this disorder (Brown & Hoadley, 1999). Many researchers are now characterizing it as a neurodevelopmental disorder, rather than a degenerative disease (Brown & Hoadley, 1999; Schanen, 1999). For example, Brown and Hoadley (1999) note that the absence of progressive neurological decreases over time as well as an absence of gliosis indicate that while brain functioning is severely impaired, this syndrome cannot be classified as degenerative. That is, brain tissue does not tend to atrophy, and cells do not die with the progression of Rett syndrome over the life span of the individual. Initially, brain size may decrease 14-34%, cortical layers may tend to thin out and atrophy of tissue may occur, however, these changes do not continue throughout the progression of the syndrome (Brown & Hoadley, 1999; Schanen, 1999). Many studies have found a plethora of physical and structural abnormalities in the brains of individuals with Rett syndrome, however, these abnormalities do not get worse with time, which is the distinction that makes this disorder neurodevelopmental as opposed to neurodegenerative (Naidu, 1997; Brown & Hoadley, 1999).
As mentioned previously, many differences have been noted in the brains of individuals affected with Rett syndrome versus unaffected individuals. As stated in Brown and Hoadley (1999), “RS is associated with dramatic neurological, neurochemical, and neruophysiological effects” (pp. 467). This book chapter includes an excellent overview of the literature in this area, as it is perhaps the most well studied topic related to Rett syndrome. Some of the effects which are discussed in this chapter include: decreased brain weight and size as compared to normal controls; decreased amounts of many different types of brain tissue (both gray and white matter in a variety of different areas, such as the cortex, caudate, putamen, and thalamus); increased cerebrospinal fluid volume; gliosis in the spinal cord, which may be involved in scoliosis and motor difficulties; problems with synaptogenic development; alterations in neurotransmitters as compared to normal controls; and many other physiological abnormalities or factors not found in unaffected controls. This chapter and many other researchers have also noted dendritic anomalies in many children with mental retardation, and in those with Rett syndrome in particular (Kaufman, 1999; Moser, 1999; Kaufman & Moser, 2000). It is not yet known how the genetics underlying this syndrome specifically lead to any of these physiological differences seen in Rett’s patients as compared to normal controls. While there are many hypotheses as to how these mechanisms function, none have been proven experimentally (Schanen, 1999). As the literature in this area is very complicated and difficult to understand without a strong background in science, this chapter provides a simple overview to orient the reader to the types of variables that have been or are being researched with regard to the neurology that underlies Rett syndrome. For the more sophisticated reader, this chapter provides a helpful starting point and cross referencing from its bibliography may be helpful. This chapter also addresses diagnostic criteria, stages of the disorder, treatment, genetic aspects of Rett’s, case studies, and other helpful information. As it is quite recent (1999) it may be a good place for the inexperienced reader to begin learning about Rett syndrome and will surely offer some new information to the reader who is more well versed in the literature in this area.
The etiology of Rett Syndrome continues to baffle researchers and scientists in spite of recent breakthroughs in genetic research. To date, a gene mutation has been discovered which appears to be responsible for Rett syndrome, but little is known about how and why the mutation occurs or how it leads to abnormal development. Much of the research is currently focused on learning more about how the mutation on MECP2 occurs and the mechanisms by which is leads to abnormal development. This will likely continue as the course of research until more is learned about how this gene operates in both females and males. Many researchers in the field, as well as active members in the International Rett Syndrome Association, are now encouraging parents of prematurely deceased girls with Rett Syndrome to have autopsies done immediately to aid in the research in this area, which will hopefully lead to an eventual cure for this devastating disorder (Van Acker, 1997). In addition, many researchers are also suggesting that girls with a clinical diagnosis participate in genetic studies if possible to further the research in this area, and warn that diagnosticians should be particularly careful in diagnosing girls with Rett syndrome because more and more of them are participating in this type of research (Shanen, 1999). As the prevalence of Rett syndrome is so low, misdiagnosis has the potential to lead to incorrect research findings, which could have deleterious effects on many areas of research on this disorder.
Return to Top
Because Rett syndrome is a relatively newly
recognized phenomenon, assessment strategies to identify the disorder are
not always straightforward. Given that it is a developmental disorder,
it may take clinicians and physicians longer to identify due to the progression
of symptoms. It is often difficult to diagnose in infancy due to the fact
that development is considered "normal" for an extended period of time
before the onset of the first observable signs. In addition, the first
observable symptoms frequently present as another disorder, most often
early infantile autism. According to Witt-Engerstrom and Gillberg (1987),
approximately 78% of girls with Rett's have been previously misdiagnosed
as having infantile autism.
Several approaches to the assessment of Rett syndrome are identified in the literature. Table 1 includes a list of assessments recommended by various authors. Volkmar describes a comprehensive and multidimensional method for assessment of Rett syndrome patients (Volkmar, 1996). The author recommends a multifaceted approach by an experienced interdisciplinary team in assessing Rett's. He suggests that many professionals may be needed in the process, such as child psychiatrists and psychologists, pediatric neurologists, speech pathologists, occupational and physical therapists, orthopedists, and most importantly, parents/primary care providers. The assessment should begin with a review of the child's developmental history, including the mother's pregnancy, the child's neonatal period, and family medical history. Neurological concerns may warrant an electroencephalogram (EEG), a computed tomography (CT), or magnetic resonance imaging (MRI) scan.
To help determine the level of a child's functioning, psychological and communicative assessments are recommended. However, traditional cognitive tests are not readily utilized, especially in the case of young children, due to some individual’s language and motor deficits. The author recommends the following instruments instead: 1) the Bayley Scales of Infant Development (Bayley, 1993), 2) the Uzgiris and Hunt Scales with Dunst's norms (Dunst, 1980; Uzgiris and Hunt, 1975), 3) the Leiter International Performance Scale (Leiter, 1948), and 4) the Merrill-Palmer Scale (Stutsman, 1948). For those children thought to be functioning in the very low range, some recommended communication scales include: 1) the Receptive-Expressive Emergent Language Scale (REEL; Bzoch and League, 1971), 2) the Sequenced Inventory of Communicative Development (SICD; Hedrick et al., 1975), and 3) the Reynell Developmental Language Scales (Reynell & Gruber, 1990). In addition, the Vineland Adaptive Behavior Scales (expanded form; Sparrow et al., 1984) administered in a semi-structured format with the parents can help identify functioning levels in the areas of communication, daily living skills, socialization, motor skills, and maladaptive behavior.
Finally, Volkmar (1996) emphasized that direct observations and interviews with parents are extremely beneficial. The parents should be asked questions related to the child's social skills, communication, responses to the environment, and motor behaviors. In addition, historical data should be collected through parent recollections, and possibly the aid of home videos, baby books, diaries, etc., that may help to identify developmental progression.
The assessment of a potential Rett syndrome patient poses many challenges for members of the multidisciplinary team. Researchers have explored some of the reasons that these challenges arise, and have proposed alternative ways to conduct assessments. For example, Demeter (2000) discussed some important factors to consider when assessing possible Rett syndrome patients. Specifically, he recommend assessing individuals via observations in multiple environments to discover differences in functioning and interactions that may be based on stimuli that exist in some settings, but not others. In addition, he notes that relying on responses that do not require fine motor skills, such as eye pointing, may yield more accurate information. Similarly, it may be important to modify assessment practices such that they rely less on material objects and more on social interactions. Such interactions seem to be more motivating and may capture the attention of the patient more so than material objects. The author states that in order to accurately assess an individual with Rett syndrome we must, “look to the interests of these girls, and use them to get a more complete image of their information processing capacity” (pp. 230).
Demeter (2000) also addresses some of the difficulties with classic intelligence tests. Tests which are considered reliable and valid for typically developing populations may not be appropriate for an individual with Rett syndrome. The author states that tests, such as the Bayley Scales (Bayley, 1993) and the Uzgiris and Hunt Scales (Uzgiris & Hunt, 1975), “may be appropriate indicators of the child’s ability to act on the environment, but not for making assumptions about the child’s cognitive skills in general” (pp. 230). These tests also may not account for the small, but meaningful, advances which parents and others report that girls with Rett syndrome make. Finally, the author concludes that it is not possible to develop a standardized test to use with Rett syndrome girls. Instead he suggests that questionnaires used with parents, teachers, and others who know the individual can yield useful information about, “the domains of life about which they have built up knowledge, the characteristics of stimuli which have meaning for them and the (often very subtle) changes in behavior which are the consequence of the learning process” (pp. 231). As demonstrated by the directly conflicting opinions in these two articles (Volkmar, 1996; Demeter, 2000), research in this area is inconclusive and controversial.
Other authors have done similar research on assessment of cognitive ability in particular. For example, Perry, Sarlo-McGarvey & Haddad (1991) compared Cattell Infant Intelligence Scale scores (intelligence test performed with individual with Rett’s) to Vineland Adaptive Behavior Scale scores (parent report measure) and found that the scores on the Vineland were significantly higher than those on the Cattell. The authors debate in their discussion, however, about whether this result indicates that the Cattell scores underestimated ability, or that the parents were biased in their reporting on the Vineland, such that they elevated their daughter’s scores. This debate appears to be inconclusive in the field, and more research is necessary.
Many other researchers have noted the difficulties in using traditional intelligence assessments with girls with Rett syndrome (Perry, et al., 1992; Woodyatt & Ozanne, 1992). Zwaigenbaum & Szatmari (1999), suggested that while most girls with Rett’s can demonstrate understanding of object permanence, they may not have the ability to manipulate testing materials used in standard intelligence tests. They suggested that one of the most functional skills in Rett syndrome may be shifting eye gaze to a novel stimuli, and that incorporation of this skill into testing situations may be useful. They also noted, however, that in a study which used such methods, the participants still performed at the level of a young infant (von Tezchner, et al., 1996). The authors conclude that the available evidence suggests that the vast majority of girls with Rett syndrome have profound cognitive disabilities by the time the reach school age (Zwaigenbaum & Szatmari, 1999; Hagberg, 1995; Iyama, 1993) in spite of the difficulty in accurately assessing them.
The assessment process must be very detailed before making a diagnosis of Rett syndrome, as this disorder often goes undiagnosed or misdiagnosed (Volkmar & Lord, 1998). During the preschool years Rett syndrome is often mistaken for autism, as the symptoms during stage two of Rett’s are markedly similar to the diagnostic criteria for autism. Making a differential diagnosis can be difficult and it is important to be aware of the distinctions between these two disorders (Van Acker, 1987). In an article by Van Acker (1987), the author attempts to differentiate between diagnosing Rett's and Autism. He highlights that Rett's is often misdiagnosed as Autism, but certain characteristics may distinguish the two. He suggests that assessing a child's motor development could be an important means for making accurate differential diagnoses. Specifically, in Rett’s patients both communicative and motor skills simultaneously regress, while any regression that occurs in autism will be verbal only. Assessment in other areas should include: 1) respiratory patterns, 2) ability and speed of movements, 3) purposeful hand movements, 4) degree and type of stereotypical movements, 5) ability to acquire new skills, 6) physical development, and 7) overall developmental milestones. Due to the developmental progression of the disorder, the author cautions that a diagnosis of Rett syndrome should remain tentative until after ages three to five years, allowing for the development of the symptoms which may confirm or rule out Rett's.
Other authors have suggested that any girl under the age of two years who displays autistic features should be evaluated for Rett syndrome (Zwaigenbaum & Szatmari, 1999). This suggestion is made in the interest of accurate differential diagnosis. By age two an individual with Rett’s may only be displaying autistic-like symptoms and many of the physical symptoms of Rett syndrome may not yet be manifested. This lack of physical Rett symptoms may further confuse the distinction between the two disorders, and waiting for more development to take place may make differential diagnosis much clearer.
Certain criteria can be used to rule out Rett Syndrome (Van Acker, 1987). These include: 1) the presence of growth retardation during the prenatal stage, 2) overdevelopment of organs, 3) eye disease and optic nerve shrinkage, 4) very small head circumference at birth, 5) brain damage acquired at birth, 6) evidence of identifiable growth or progressive nerve disorder, and 6) acquired nerve disorder resulting from sever infection or head injury.
Rett syndrome is a relatively rare disease; therefore, physicians may not consider looking for Rett syndrome criteria in the initial stages of diagnosis. Initially, Rett’s may be misdiagnosed cerebral palsy, epilepsy, Angelman syndrome (Ellaway, et al., 1998), or even as a childhood psychological disorder. In later stages of development, professionals may explore the possibility of ataxia, cerebral palsy, spinocerebellar degeneration or unknown degenerative disorder diagnoses (Association of Genetic Support of Australia, 1996).
Given the nature of this disorder, a developmental approach is necessary in the assessment and identification of Rett syndrome. This approach requires continuous observation and documentation of the individual’s medical history. Physical and neurological status must be evaluated in order to correctly identify Rett’s. It is important to recognize the range of "normal" development within each domain. Of particular importance is the regression of any acquired skills or inability to gain new skills. Exclusion criteria, such as brain damage acquired at the time of birth, nerve disorders that result from infections or head injuries, etc., is used to aid in the process of ruling out Rett's. In addition, as many authors have noted, it is important not to make a conclusive diagnosis until enough development has occurred to rule in or rule out Rett syndrome.
Given that no biological marker has been identified in Rett's, a quick chromosomal test cannot yield the valuable information needed to identify the disorder. Although researchers are working on developing such a test based on recent genetic findings, to date nothing has been made available to the public and more research is needed in this area (International Rett Syndrome Association, 1999; Glasson, et al., 1998; Mazzocco, et al., 1998). Until the science in this area progresses further, a multifaceted approach in the assessment of Rett's is indicated. The first step is to discuss the child's developmental history and family medical history with a well-trained clinician or physician. Reflecting on early development and possible use of written diaries, baby book journals, and home videos may yield important information (Fiumara, et al., 1999). An assessment of the child's communication functioning, including receptive, expressive, and nonverbal language is crucial given that loss of speech, or inability to acquire speech, is one of the criteria for the disorder. Finally, as research on accuracy of traditional assessment methods is inconclusive and controversial, such tools must be used with caution. It is important to include observation and parent report measures when assessing a possible Rett syndrome patient.
Return to Top
Currently there are no available therapies
which change the process of Rett syndrome or its natural history (Zwaigenbaum
& Szatmari, 1999). Interventions are aimed at preserving physical
and psychosocial functioning, enhancing quality of life, and providing
education and support to families, educators and other interventionists.
Efficacy of intervention is these areas is not well documented, however,
and most findings are based on case studies and individual experiences,
rather than controlled clinical trials (Zwaigenbaum & Szatmari, 1999).
Treatment of Rett's is often similar to the treatment of autism in some
ways, however, traditional applied behavior analysis (ABA) approaches that
are often used with autism may have limited effectiveness with Rett’s individuals
(Brown & Hoadley, 1999; Evans & Meyer, 1999; Smith, Klevstrand,
& Lovaas, 1995). Children with Rett’s are frequently placed in
special education, and receive other assistance such as behavior modification,
pharmacotherapy, and other treatment modalities to encourage acquisition,
or reacquisition, of basic adaptive skills, such as making desires known
self-feeding and various motor skills. For Rett syndrome the services
of other professionals, such as occupational, physical, and respiratory
therapists, have greater importance than for children with autism, due
to the severe impairment within these domains (i.e., loss of purposeful
hand movements, limited motor skills, apnea, etc.). Providing information
to teachers and special educators about these conditions is often helpful
for the child in school. In addition, nutritional consultation may
be helpful if weight gain appears to be problematic for the child.
Many girls with Rett's experience constipation and their bowels may become
impacted due to failure to consume adequate fluid and fiber. Dietary
modification may alleviate the symptoms. Some examples of common
modifications are adding mineral oil or high liquid content fruit, however,
artificial laxatives, enemas, or suppositories are often required.
While behavioral interventions are often tried with individuals with Rett syndrome, recent research indicates that such approaches may not be effective in many cases (Evans & Meyer, 1999; Smith, Klevstrand, & Lovaas, 1995). One such study (Smith, Klevstrand, & Lovaas, 1995) found little improvement in three girls with Rett syndrome who received intensive behavioral intervention in a one-on-one discrete trial format followed by a group format. Two of the girls received intensive treatment (ten hours per week) for two years and the third received it for eight months (30 hours per week). The researchers reported that the subjects performed in the moderate to severe range of mental retardation at intake, and their functioning declined to the point that they were no longer testable at posttreatment. While two of the subjects made moderate progress in some areas (behavior problems, toileting, communication), the researchers reported losses in other areas (lack of responsivity, verbal articulation, ability to feed self) which significantly offset the treatment gains. Additionally, the third subject did not make any reported progress while in treatment. The authors concluded that behavioral intervention is not promising for individuals with Rett syndrome. They also noted that this lack of success of behavioral interventions makes differential diagnosis of autism and Rett’s very important, as the individuals in their study received this intensive treatment program because they were mistakenly diagnosed with autism.
Some researchers have suggested that tantrums may be the only area in which behavioral interventions are effective for individuals with Rett syndrome (Brown & Hoadley, 1999; Smith, et al., 1995). Various behavioral techniques have been used with success in this area, although the researchers note that their findings must be interpreted with caution, as individuals with Rett’s tend to tantrum less as they get older anyway.
Another study by Evans and Meyer (1999) found some similar results to Smith, et al. (1995), but also documented some new and interesting findings regarding treatment of individuals with Rett syndrome. This study examined the relationship between various excess behaviors (hand-wringing, inappropriate vocalizations, body rocking, staring) and environmental conditions for one individual with Rett syndrome. The treatment was conducted in two phases. During the first phase they tried to teach the participant three purposeful skills using behavioral type interventions: 1) crossing her arms to indicate desire for a hug, 2) playing an electronic flute instead of engaging in hand-wringing, and 3) engaging in a voluntary hand movement, mainly running her hands through a bowl of dry rice. The authors reported that their findings were disappointing in that there was no evidence of acquisition of any of the three behaviors being taught.
The researchers found, however, that some conditions in the individual’s school day seemed to be associated with reductions in her behavior excesses. Specifically, low demand, positive social situations were found to be related to reduced hand mannerisms. Based on these observations, they conducted the second phase of the study in which two procedures were carried out and evaluated for effect on behavior. One such procedure involved playfully engaging with the participant as long as she appeared to be enjoying the interaction. The second procedure was to use this type of positive social interaction to try and teach a purposeful hand movement. The researchers hypothesized that because the participant enjoyed this type of interaction she may be more motivated and less frustrated, thus increasing her ability to learn a new hand movement. Results were somewhat promising for this phase of the study. Specifically, several of her behavioral excesses (hang-wringing and body rocking) significantly decreased during the social interaction phase of intervention. Decreasing demands and increasing positive social interactions seemed to have a significant impact on these behaviors. Additionally, the participant made several spontaneous hand movements during the several months of intervention. While these responses were sporadic, and treatment gains did not maintain, in previous intervention phases she had not made any attempts at purposeful hand movements.
The authors conclude this article with several interesting points about individuals with Rett syndrome. First, they acknowledge that their findings are extremely limited and that a great deal of effort was put forth to elicit this information. Second, they note that a significant implication for their findings lies in the types of changes that showed some success. Specifically, the ecological changes (modification of interaction style) appeared to be the most significant, while teaching alternative skills proved to be extremely difficult. This finding has important implications for future research. Examining ecological factors may be a more promising intervention strategy for individuals with Rett syndrome than trying to teach new skills. A third area of interest noted by the authors lies in looking at the few spontaneous behaviors that individuals with Rett syndrome may engage in. For example, they noted that their participant would often stare at a desired objects, but that she would never reach for them or make any other indication that she wanted something until someone gave the object to her. The authors state that such subtle behaviors may have important functional significance and should not be ignored. Similarly, the authors note that behavior excesses, although they appear to be involuntary much of the time, often increased in situations that were unpleasant from the individual’s point of view. As a result, these behaviors can be interpreted as indicators of unhappiness in some situations and should be examined more closely under such hypotheses. Finally, because positive social interactions seemed to be the most significant predictor of decreased stereotyped movements, the authors suggest that future research and interventions should focus on facilitation of positive and meaningful relationships for individuals with Rett syndrome. Very little research has been done in this area, although the authors cite one study in which a successful friendship for an individual with Rett’s was reported (Meyer, et al., 1998).
Other authors have noted that focusing intervention on development of existing skills may be more promising than trying to teach new skills to individuals with Rett syndrome (Sandberg, Ehlers, Hagberg, & Gillberg, 2000). One such study closely examined the symptoms of a group of Rett’s patients, focusing on cognitive and language abilities and autistic-like behaviors (Sandberg, Ehlers, Hagberg, & Gillberg, 2000). Based on their findings, they recommend targeting joint attention and gestural communication in intervention, as these were areas that many of the girls showed deficits in. In addition, they note that many of the individuals in their study spontaneously engaged in eye pointing, some gestures, manual signs, use of pictures, and some spoken language. The authors suggest that intervention which targets development of whichever of these behaviors the individual is already engaging in may be more successful than trying to teach new behaviors. As many Rett syndrome patients lose skills over time, intervention can focus on maintenance as well as development of these skill areas.
To date, there is no cure for Rett syndrome, therefore, much of treatment is focused on symptomatic relief. Since there is no biochemical marker, pharmacological treatment (DELETE and replace with my sentence has its limitations) is limited. One of the primary reasons for medicating individuals with Rett syndrome is to control seizures and prevent further brain impairment. (DELETE and replace with previous sentence in bold Much of the medications used with Rett's patients is for seizure control to prevent further brain impairment.) Many clinicians use Tegretol as the drug of choice for seizure management. Research has shown, however, that girls with Rett's may experience a decrease in seizure activity as they enter late adolescence, allowing for modifications of their medication regimen over time. Treatment of seizures should not be initiated until confirmation of abnormal brain activity is documented through an EEG.
Other drug treatments have been investigated in an attempt to ameliorate symptoms and increase adaptive functioning. However, many of the results are time-limited, inconsistent, and replication of any positive results is still needed. In addition, sample sizes are very small, often times only a case study, making it difficult to make generalizations and conclusions about the treatment. Bromocriptine, a dopamine agonist, initially showed improvements in communication and a decrease in frequency of agitation episodes, but these gains were not maintained (Zappella, 1990; Zapella, Genazzani, Fachinetti, & Hayek, 1990). Administration of tetrabenazine, a monoamine depleter and blocker, was followed by an exacerbation of the symptoms (Sekul & Percy, 1992), while magnesium orotate or citrate resulted in a decrease in hyperventilation for a few girls with Rett's (Egger, Hofacker, Schiel, & Holthausen, 1992). Naltrexone, an opiate antagonist, resulted in no improvement (Percy, et al., 1991), while Matsuihi et al. (1994) reported positive effects with the abnormal respiratory condition. This study also indicated, however, that in 40% of the girls, there was a decline in motor functioning and rapid progression of the disorder even though they were on the medication.
A variety of other research exists regarding possible medications for a multitude of symptoms related to Rett syndrome. For example, one study looked at the effects of melatonin on sleep patterns in individuals with Rett syndrome (McArthur & Budden, 1998). In this study, nine girls with Rett's were monitored 24 hours a day over a 10 week period via wrist actigraphy. Baseline was assessed for one week indicating irregular sleep-wake patterns. The girls underwent a 4-week melatonin treatment period in a double-blind, placebo-controlled, crossover protocol which included a 1-week washout between trials. The girls' patterns prior to treatment were poor compared to healthy girls. However, melatonin treatments significantly improved their sleep time and sleep efficiency. No adverse side effects were noted, yet long-term effects of melatonin use in pediatric clients are unknown at this time.
In a similar study, the authors examined the effects of L-carnitine on Rett symptoms (Plioplys & Kasnicka, 1993). This was a case study involving a 17 year-old girl diagnosed with Rett Syndrome. She was given L-carnitine (50/mg/kg/day) and after two months she reportedly engaged in more eye contact and showed improved alertness. She also demonstrated an increased interest in her environment, began reaching for objects, and was able to respond with one or two words to simple questions. When the L-carnitine was removed, she reportedly withdrew into her pretreatment state, including poor eye contact, limited interest in her environment, inability to speak, and lethargy. One week after readministration of the L-carnitine, the patient resumed her post-treatment affect and ability to respond verbally with one to two words. Even with these positive treatment effects, replication of these results is still needed.
This line of research has continued with varying levels of success. One replication of the 1993 study (Plioplys & Kasnicka, 1993) found similar results (Ellaway, Williams, Leonard, Higgins, Wilcken, & Christodoulou, 1999). This study investigated the effect of L-carnitine using a randomized, placebo-controlled, double-blind crossover trial with 35 participants. The researchers measured several variables at pre and posttreatment using the Rett Syndrome Motor Behavioral Assessment, the Hand Apraxia Scale, and the Patient Well-Being Index. Result showed a significant increase in well being and improvement in hand apraxia for the individuals in the L-carnitine condition at follow-up. The authors note that their results are limited by the power of their study, but suggest that L-carnitine should not be ruled out as a possible treatment for Rett syndrome. Finally, they noted that although L-carnitine did not lead to major changes in functioning, the types of small changes that they found could still have a significant impact on individuals with Rett syndrome and their families. This finding indicates that this line of research should be continued, as more information is necessary before this treatment could make an impact on the treatment of Rett syndrome.
Other areas of research have attempted to teach new skills to individuals with Rett’s and have also been aimed at symptom management. Communication is an area of particular need for girls with Rett's since most will be unable to communicate verbally. Building upon the girls' communication abilities, such as eye gaze and facial or gestural behaviors, is a common strategy. Augmentative communication systems involving eye pointing, communication/picture boards, facial expressions, gestures, and the activation of switches or computers have been utilized with some individuals (International Rett Syndrome Association, 1990; Zwaigenbaum & Szatmari, 1999). In addition, speech and language specialists should be consulted for help in program planning.
It has been suggested that speech therapy may be more helpful for girls with Rett syndrome in maintenance of chewing and swallowing than for facilitation of actual language (Brown & Hoadley, 1999). Many individuals with this disorder have great difficulty with eating to the point that they become severely malnourished. While speech therapy may aid in maintenance of these skill areas, many individuals will ultimately need a supplementary feeding tube to maintain normal weight. Consultation from a dietician or nutritionist may be necessary to prevent and handle problems in these areas.
Physical and occupational therapists can provide additional support for individuals with Rett syndrome. Intensive therapy, although it most often will not alter the course of the disorder, may help in alleviating or minimizing some of the orthopedic symptoms. In fact, Brown and Hoadley (1999) suggest that physical therapy for apraxia is critical. Specifically, these types of therapy may help improve functional movement or mobility and prevent deformities (IRSA, 1989). Many individuals with Rett syndrome develop scoliosis or kyphosis (hunchback) and physical therapy may be helpful in slowing progression in these areas (Brown & Hoadley, 1999). Treatment of apraxia/ataxia may include use of a therapy ball, balance-stimulating floor activities, segmental rolling, rotation and weight-shift activities, or possible vestibular stimulation activities (such as swinging; Brown & Hoadley, 1999). These types of physical therapy activities have been suggested for maintenance and development of gait as well (Brown & Hoadley, 1999). Treatment addressing stereotypic hand movements includes splinting (Aron,1990; Brown & Hoadley, 1999), music therapy, behavioral approaches (although they may be ineffective; Brown & Hoadley, 1999), operating toys with switches and simply holding the individual’s hand (Brown & Hoadley, 1999).
In a book chapter, Zwaigenbaum and Szatmari (1999) provide a brief overview of some of these types of services. Regarding behavior therapy, they note that operant conditioning techniques have been used to decrease self-injurious behavior, but that such interventions are often labor intensive and impractical. Additionally, they note that similar techniques have been used to teach feeding skills, and that paired with elbow splints for functional positioning of arms, this intervention was somewhat successful. Other researchers have found similar levels of success in use of behavioral principles to teach self-feeding (Brown & Hoadley, 1999; Piazza, Anderson & Fisher, 1993) as well as other skills, such as ambulation and use of an adaptive switch (Bat-Haee, 1994). In relation to intervention targeted toward communication, Zwaigenbaum and Szatmari (1999) state that a focus on the fundamentals of communication, rather than speech specifically, may yield more successful results. These fundamentals include behaviors such as eye contact, eye pointing and facial expression. These authors discuss rehabilitation therapy (physical and occupational) as most relevant for optimization of functioning, prevention of deformities, and maintenance of movement and ambulation for as long as possible. They note some success with use of hand and elbow splints to decrease progression of spasticity and interrupt stereotypic behaviors. In addition, they suggest that these types of therapists may aid with adaptive equipment for daily living, ideas for appropriate toys and play, and assessment and management of feeding problems. These and other authors (Brown & Hoadley, 1999) also suggest that music therapy, hydrotherapy, horseback riding and massage may have some therapeutic success, although research in these areas is sparse and inconclusive.
As noted in the chapter by Zwaigenbaum & Szatmari (1999), other research has looked at various methods of symptom management. One such study examined the use of elbow splints for their ability to inhibit stereotypic hand movements in patients with Rett Syndrome (Aron, 1990). The elbow splints restricted approximately 75% of movement, therefore preventing self injurious behavior. The study examined eight girls between the ages of two and fourteen years old. The girls wore the splints continuously, except during feeding for those patients that were able to feed themselves, and most girls did not wear the splints while sleeping. In addition to preventing injuries, the splints prevented hand wringing. Caretakers also reported increased social interactions, as a result of decreased distraction from non-purposeful hand movements. Reports from professionals and parents indicate that the splints enabled patients to grasp objects and use a walker, and led to decreased agitation, and better comprehension of the environment.
In a related study, physiotherapists used massage techniques on the neck and jaw of six girls with Rett Syndrome, ages three to sixteen years old (The International Rett Syndrome Association, 1989). The experimenters took pre and post test measures of muscle tone, range of movement, and pain reaction. Observations of teeth grinding were taken each day as well. The treatment consisted of two twenty minute sessions, twice a week for six weeks. Results showed reduced muscular pain, reduced tension in the jaw, and some reduction of teeth grinding. Findings did not indicate increased range of motion in the neck.
Finally, prognosis for Rett syndrome is worse than autism so additional support for parents, siblings, and family members will likely be necessary (Zwaigenbaum & Szatmari, 1999). Long-term support for the family, such as counseling and respite may be beneficial due to the increased stress in their lives. In addition, it has been suggested that counseling for family members regarding appropriate placement for individuals with Rett syndrome as they get older may be helpful (Brown & Hoadley, 1999). The International Rett Syndrome Association (IRSA) may be a helpful avenue for families and educators to obtain information, support and ideas about how to manage caring for an individual with Rett syndrome (Zwaigenbaum & Szatmari, 1999).
There is no single treatment for Rett's disorder to date. Treatment must include a multi-dimensional approach which addresses the individual's needs at her stage of development in Rett's. Treatment should focus on alleviating or minimizing symptoms associated with the disorder. If the individual develops seizures, appropriate medication should be administered after a careful EEG confirms seizure activity. Augmentative communication should begin early in the child's life as oral communication will usually become extremely limited or nonexistent. Physical and occupational therapy will help with motor skills and mobility, while a nutritionist should be consulted for weight gain and dietary concerns. Finally, ongoing support groups, counseling, and/or respite should be provided to family members to help deal with the stress of caring for an individual with Rett syndrome. Additional considerations are educating the child's key social agents (i.e., teachers, family, and friends) on characteristics and developmental trajectories of Rett Syndrome.
There is no cure for Rett's, and therapeutic interventions directed at its fundamental mechanisms have failed to demonstrate any lasting of substantive improvements (Van Acker, 1998). Replication of studies continues to be problematic. As Van Acker (1998) states, "given the lack of a biochemical marker and a rather limited understanding of the biological basis of Rett Syndrome, the ineffectiveness of drug therapy is not particularly surprising." Although interventions have historically been limited in success, increased awareness and research in the area of Rett's will likely produce interventions with increased effectiveness. Until or if a cure is ever found, treatment will continue to address the symptoms associated with Rett's.
Rett syndrome is a complex neurodevelopmental disorder, which affects primarily girls with onset early on in life. While a great deal of progress has been made in the area of etiology, many questions remain unanswered and further research is necessary. As Rett syndrome is characterized by regression and loss of skills over time, it is very important to consider a developmental perspective in assessment, diagnosis and treatment planning. Further, because early symptoms can also be characteristic of autism, diagnosis should not be conclusively made prior to age five. Assessment of individuals with Rett syndrome remains difficult due to lack of skills that are necessary to carry out many traditional assessment tools. In addition, current knowledge about treatment is vague and inconclusive. Because each individual with this syndrome may progress through the stages at a different rate and may have varying levels of impairment, treatment and intervention needs to be individualized and developmentally appropriate. There appears to be a wide variety of research emerging in the area of Rett syndrome, which bodes well for the future of our knowledge about this disorder.
As research on Rett syndrome is relatively sparse and many variables are still unexplored, the internet may offer a unique opportunity to obtain the latest information on this syndrome. Due to the lag time inherent in the publication process, the internet may be a more efficient way to obtain information.
Genetic research in particular may be something that individuals outside the fields of medicine and science may not have access to. As a result, the internet becomes a particularly helpful tool when researching these areas. In addition, many journal articles that address genetics are so technical that people outside the field may have a very difficult time understanding them. Assessment and treatment of Rett syndrome are also not clear cut, and can be difficult and frustrating for individuals looking for a diagnosis and treatment plan that makes sense. The internet may be a useful resource in this area as well. The following websites may contain information regarding the genetics, physiology, assessment and treatment of Rett syndrome. They are written at varying levels such that individuals reading them may or may not need background knowledge in science. While some of the sites may not be related specifically to Rett syndrome, they still contain information relevant to these topics that may be helpful to parents and professionals in general.
The Australian Rett Syndrome Homepage. Caratine as a Treatment
for Rett Syndrome.
This page also could not be found, however the page listed below is the Australian Rett Syndrome Home Page. Replace this with the one below in bold.
A brief discussion of Caratine as a treatment to improve overall behavior in Rett Syndrome patients. Parents and teachers are involved in providing feedback in the project. To date the study being conducted at The New Children's Hospital in Sydney is limited. However, one patient exhibited significant improvement.
The Australian Rett Syndrome Home Page: http://www.general.uwa.edu.au/u/hleonard/Welcome.html
This page offers all types of information about Rett syndrome. It appears to have been updated very recently. It contains information about current research on Rett’s in Australia, diagnostic criteria, signs and stages of Rett’s, contact information for many types of organizations and clinics, research sites and much more. It appears to be a good thorough resource for families and lay people who do not have a great deal of scientific or medical background.
Department of Neurology at Baylor College of Medicine. Rett Syndrome
The Blue Bird Circle Clinic for Pediatric Neurology (at Baylor College of Medicine): http://www.bcm.tmc.edu/neurol/struct/blueb/blueb2.html
The Baylor College of Medicine site provides a wide range of information about many programs at the college. It has some useful links to sites about clinics and research at the college which are directly related to Rett syndrome. The Blue Bird Circle clinic is a center that specializes in Rett’s. The Rett Syndrome Center is a partnership between The Baylor College of Medicine and the Texas Children's Hospital. Research is funded by the National Institute of Health and the International Rett Syndrome Association. This center is made up of a collaboration of professionals, specializing in neurology, molecular genetics, orthopedics, communication, audiology, epidemiology, gastroenterology, and nutrition. This site also offers a faculty page describing research interests and publications. Specializations include drug and non medical treatment for refractory seizure disorders, sleep disorders, neurogenerative diseases, and hereditary ataxias. In addition, Baylor College is involved research and treatment of seizures and useful information on this topic can be found at this site.
Gene Today…Gone Tomorrow: http://www.rettsyndrome.org/main/announcement.htm
This website is an excellent one for individuals who would like to learn more about the etiology of Rett syndrome, but do not have a background in science. It contains a simple explanation of recent research findings on the MECP2 gene. In addition, it defines and explains terms which non-science oriented individuals may not be familiar with. It is an excellent place to start for those individuals who would like a general understanding of the genetics of this disorder, but who do not have a background in science.
The International Rett Syndrome Association: http://www.rettsyndrome.org
This is perhaps the most helpful of the websites on Rett’s. This website offers many different sorts of information and is very up to date. The site provides a mission statement and information about the board, officers, and membership. Information about Rett Syndrome includes diagnosis, education, treatment, and personal stories. It appears that it has been updated as recently as sometime during the year 2000. The site map contains many different choices of topics related to Rett’s, all of which appear to be comprehensive and thorough. Topics include current research, personal stories, sources of information, intervention strategies and more. There are many direct www links to related resources such as, on line magazines for parents of children with special needs, advocacy, disability related sites, foreign sites, understanding the Individual Education Program (I.E.P.), and the National Parent Network on Disabilities. Support links include information on publications, T-shirts, videos and other materials. This is also a good place to search for current events, music benefits, and conferences for children with Rett Syndrome and their families. The website is user friendly and easy to navigate.
Living with Rett: http://members.aol.com/Rsmother/sitemap.html
This site offers information based on the experiences of a mother whose child has Rett syndrome. It appears to contain useful information, especially for parents who are just learning of their child’s diagnosis. In addition to providing factual information, the site contains quotes, stories, photos, and other similar items which parents and others may find inspirational in dealing with the difficult news that a child has a serious disability. The only drawback to this site is that it does not appear to have been updated since May, 1999, and therefore, the factual information contained on it is nearly two years old.
The National Academy for Child Development: http://www.nacd.org./
This is an international organization dedicated to helping children and adults reach their full potential. This site discusses treatments and programs for a diverse range of developmental disabilities, genetic syndromes and other types of disabilities, as well as for gifted individuals (DELETE and replace with previous sentence in bold issues from disabilities to giftedness). It offers general information about the design of neurodevelopmental home programs for individuals of all ages of the lifespan. In addition, the site explains how to obtain services from this organization, where their sites are located, what the fees are, etc. The organization is comprised of parents and professionals. The site includes a forum for parents to share information and testimonies regarding drug treatments and home care for their children. Additionally, professionals provide maps of the various service areas, describe the different levels of evaluation, and how to make an appointment with an evaluator.
National Center for Biotechnology Information: Rett Syndrome:
This website offers very current descriptions of research on Rett syndrome. It is somewhat technical, as much of the research is biological/physiological in nature, but very up to date. The site is divided into different topic areas such as clinical features, population genetics and inheritance, and is easy to navigate. In each of these topic areas research is reviewed starting with early studies and leading up to research as recent as 1999. Citations are provided for all research, with the option to order articles if interested.
Online Mendelian Inheritance In Man (National Center For Biotechnology
This page contains extensive information about current research on Rett syndrome. It contains many references and abstracts about current research, is very comprehensive and appears to be up to date. It may be somewhat technical for the non-science oriented person, but is a good place to start when looking for original research articles on this topic.
Our Rett Syndrome Page: http://www.bundlings.com/irsg.htm
A comprehensive site which includes information about Rett Syndrome, newsletters, and gift ideas. This site also includes parent tips about toys, adaptive clothing, toileting, transportation, computers, etc. Parents may find the model for an informational letter useful. This letter is meant to inform family and friends about the initial diagnosis. It explains what Rett Syndrome is and how to ask for support. This site contains addresses for other helpful web sites, photos, picnics, conferences, and a cookbook complied by parents of daughters with Rett Syndrome. Proceeds benefit the Rett Foundation.
Rebecca led a full and interesting life, despite having Rett syndrome:
This is a nice site for parents who want tips for providing an enriched environment for a daughter who has Rett Syndrome. The P.A.T.H. Planning process recommends forming a core group of supportive family, friends, and professionals who will meet to discuss goals and their implementation. Plans include short-term and long-term social goals and school inclusion strategies for children with Rett Syndrome. Visitors to the site are encouraged to contact siblings who have a sister with Rett syndrome via e-mail. This site focuses on strength and resiliency. An inspirational essay by Kathy Hunter, the founder and president of the International Rett Syndrome Association and other writings are included. She writes, " I often think about the paradox of 'disability.' I have found (with apologies to Newton!) that for every disability there is a an equal and opposite ability."
Rett Syndrome: http://www.rettsyndrome.net/
This website is excellent, comprehensive and appears to be one of the best on the internet. It contains all types of information and is not written for a scientific audience. Individuals who want to learn about all different topics pertaining to Rett syndrome will find this website very helpful. Perhaps one of its greatest strengths is the abundance of links to other websites such as The National Institutes of Health and the Kennedy Kreiger Institute. This website appears to be up to date and will be helpful to all audiences.
Rett Syndrome (Written by Stephen M. Edelson, Ph.D., Center for the
Study of Autism, Salem, Oregon): http://www.autism.org/rett.html
This site offers a brief description of Rett syndrome and its symptoms from the Center for the Study of Autism in Oregon. As the description is very brief, the most useful part of the site lies in the materials that are available for purchase. The site offers booklets, videos and other materials on Rett’s and other related disorders, which may be helpful to parents, educators and others with an interest in this area. As it is based at a center for the study of autism, it is likely to be updated frequently with helpful and current information and research.
Rett-Syndrome Personal Pages/Experiences: http://www.execpc.com/~tamratam/personalpages.html
This is a great site for any family looking for ideas and support. It has over 40 personal web pages with stories and pictures. Each web page has its own personal touch including music, family photos and letters. Many sites encourage e-mail correspondence. This is a good place to look for information about upcoming benefit concerts and Rett Syndrome social activities.
Rett Syndrome: What is it?: http://www.isn.net/~jypsy/rett.htm
This site provides a thorough overview of Rett syndrome, reviews diagnostic criteria and lists the supportive criteria as well. It also contains many relevant links to other types of information, including recent research on Rett’s. It appears to be thorough, accurate and up to date, although brief. This site should be very helpful in providing information to individuals who are not familiar with Rett syndrome, and its links should be able to update the individual who already has some background on Rett’s, but wants more information about current research.
The Rettnet: http://www.rettsyndrom.org/topics.htm
A listserver provided to members of the International Rett Syndrome Association. Information about the RettNett and how to join is provided. The RettNett has a comprehensive list of Digests to explore. Adult Years includes a dialog between informed parents about life expectancy, respiratory difficulties, and other practical matters for daily living. Education and Learning provides information and suggestions for cognitive testing, school field trips, transitioning during and after school years, communicating with teachers, and making friends. Other Digests include Equipment, Movement and Support, Behaviors, Vacations and Outings. The Digests also provide specific information on health and medical issues, such as Dental, Heart, Brain, and Digestive System. This website appears to contain useful information and is comprehensive, however, it does not appear to have been updated in several years. As the research in this area is constantly changing, the reader is encouraged to look at other sites for more updated information.
Space Coast Early Intervention Center: http://www.scbn.com/sceic.html
This is a non-profit educational website that supports early intervention, therapy, and mainstreaming and full inclusion. This site provides information on programs for all children with and without developmental delays. The center is designed for all levels of early development beginning with infancy, and following in sequence with programs for 18 month to two year olds, toddlers, and preschool age children. Beginning with infancy, families receive an Individualized Family Support Plan (IFSP) which delineates what services they are receiving through this program. This site contains some useful general information about early intervention (prior to age five) and full inclusion. For more specifics on the programs it may be necessary to contact the center. The site also discusses family education and socialization practices.
American Psychiatric Association. (2000). Diagnostic and statistical manual of mental disorders (4th ed.-TR). Washington, DC: Author.
Amir, R. E., Van den Veyver, I. B., Wan, M., Tran, C. Q., Francke, U., & Zoghbi, H. Y. (1999). Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nature Genetics, 23(2), 185-8.
Anvret, M., & Wahlstrom, J. (1992). Genetics of the rett syndrome. Brain and Development, 14 (Suppl.), S101-S103.
Aron, M. (1990). The use and effectiveness of elbow splints in the Rett Syndrome. Brain Development. 12, 162-3.
Association of Genetic Support of Austrailia. (1996.) http://www.dircsa.org.au/pub/docs/factrett.txt
Barbi, G., Steinbach, P., & Vogel, W. (1984). Nonrandom distribution of methotrexate-induced aberrations of human chromosomes: detection of further folic acid fragile sites. Human Genetics, 68, 290-294.
Batt-Haee, M. A. (1994). Behavioral training of a young woman with Rett syndrome. Perceptual and Motor Skills, 78, 314.
Bienvenu, T., Carrie, A., De Roux, N., Vinet, M., Jonveaux, P., Couvert, P., Villard, L., Arzimanoglou, A., Beldjord, C., Fontes, M., Tardieu, M., & Chelly, J. (2000). MECP2 mutations account for most cases of typical forms of Rett syndrome. Human Molecular Genetics, 9, 1377-1384.
Braithwaite, K. (1997). The potentially handicapping effects of Rett syndrome on the development of a child. http:// www.com.au/rett.html.
Brown, R. T. & Hoadley, S. L. (1999). Rett syndrome. In S. Goldstein, C. Reynolds, et al. (Eds.), Handbook of Neurodevelopmental and Genetic Disorders in Children, (pp. 459-477). New York: The Guilford Press.
Buhler, E.M., Malik, N.J., & Alkan, M. (1990). Another model for the inheritance of rett syndrome. American Journal of Medical Genetics, 36, 126-131.
Buyse, I. M., Fang, P., Hoon, K. T., Amir, R. E., Zoghbi, H. Y., & Roa, B. B. (2000). Diagnostic testing for Rett syndrome by DHPLC and direct sequencing analysis of the MECP2 gene: Identification of several novel mutations and polymorphisms. American Journal of Human Genetics, 67, 1428-1436.
Cheadle, J. P., Gill, H., Fleming, N., Maynard, J., Kerr, A., Leonard, H., Krawczak, M., Cooper, D. N., Lynch, S., Thomas, N., Hughes, H., Hulten, M., Ravine, D., Sampson, J. R., & Clarke, A. (2000). Long-read sequence analysis of the MECP2 gene in Rett syndrome patients: Correlation of disease severity with mutation type and location. Human Molecular Genetics, 9, 1119-1129.
Comings, D.E. (1986). The genetics of rett syndrome: the consequences of a disorder where ever case is a new mutation. American Journal of Medical Genetics, 24 (Suppl. 1), 383-388.
Deb, S. (1998). Self-injurious behavior as part of genetic
syndromes. British Journal of Psychiatry, 172, 385-388.
Demeter, K. (2000). Assessing the developmental level in Rett syndrome: An alternative approach? European Child and Adolescent Psychiatry, 9, 227-233.
Egger, J., Hofacker, N., Schiel, W., & Holthausen, H. (1992). Magnesium for hyperventional in Rett's Syndrome. Lancet, 340, 621-622.
Ellaway, C., Buchholz, T., Smith, A., Leonard, H., & Christodoulou, J. (1998). Rett syndrome: A significant clinical overlap with Angelman syndrome but not with methylation status. Journal of Child Neurology, 13, 448-451.
Ellaway, C., Williams, K., Leonard, H., Higgins, G., Wilcken, B., & Christodoulou, J. (1999). Rett syndrome: Randomized controlled trial of L-carnitine. Journal of Child Neurology, 14, 162-167.
Evans, I. M. & Meyer, L. H. (1999). Modifying adult interactional style as positive behavioral intervention for a child with Rett syndrome. Journal of Intellectual and Developmental Disability, 24(3), 191-205.
Fiumara, A., Barone, R., D’Asero, G., Marzullo, E., & Pavone, L. (1999). Rett syndrome: Photographic evidence of rapid regression. Journal of Child Neurology, 14(8), 550-552.
Glasson, E. J., et al. (1998). Diagnosis of Rett syndrome: Can a radiograph help? Developmental Medicine and Child Neurology, 40, 737-742.
Hagberg, B. (1995). Rett syndrome: Clinical peculiarities and biological mysteries. Acta Paediatrica Scandinavica, 84, 971-976.
Hagberg, B. & Skjeldal, O. H. (1995). Rett variants: A suggested model for inclusion criteria. Pediatric Neurology, 11, 5-11.
International Rett Syndrome Association (1989). Hope for Teeth Grinding. The International Rett Syndrome Association Quarterly Newsletter,1.
International Rett Syndrome Association (1990). Parent Idea Book: Managing Rett Syndrome. Fort Washington: International Rett Syndrome Association.
International Rett Syndrome Association (1999). Gene today…gone tomorrow. www.rettsyndrome.org/main/announcement.htm
Iyama, C. H. (1993). Rett syndrome. Advances in Pediatrics, 40, 217-245.
Kaufman, W. E. (1999). Cytoskeletal determinants of dendritic development and function: Implications for mental retardation. Developmental Neuropsychology, 16(3), 341-346.
Journel, H., Melki, J., Turleau, C., Munnich, A., & deGrouchy, J. (1990). Rett phenotype with x/autosome translocation: possible mapping to the short arm of chromosome x. American Journal of Medical Genetics, 35, 142-147.
Kaufman, W. E. & Moser, H. W. (2000). Dendritic anomalies in disorders associated with mental retardation. Cerebral Cortex, 10, 981-991.
Kim, S. J. & Cook, E. H. (2000). Novel de novo nonsense mutation of MECP2 in a patient with Rett syndrome. Human Mutations,15(4), 382-383.
Matsuishi, T., Urabe, F., Percy, A. K., Komori, H., Yamashita, Y., Schultz, R. S., Ohtani, Y., Kuriya, N., & Kato, H. (1994). Abnormal carbohydrate metabolism in cerebrospinal fluid in Rett syndrome. Journal of Child Neurology, 9, 26-30.
Mazzocco, M. M. M., Pulsifer, M., Fiumara, A., Cocuzza, M., Nigro, F., Incorpora, G., & Barone, R. (1998). Brief report: Autistic behaviors among children with Fragile X or Rett syndrome: Implications for the classification of pervasive developmental disorder. Journal of Autism and Developmental Disorders, 28(4), 321-328.
McArthur, A. J., & Budden, S. S. (1998). Sleep dysfunction in Rett syndrome: a trial of exogenous melatonin treatment. Developmental Medicine & Child Neurology, 40, 186-192.
Meloni, I., Bruttini, M., Longo, I., Mari, F., Rizzolio, F., D’Adamo, P., Denvriendt, K., Fryns, J., Toniolo, D., & Renieri, A. (2000). A mutation in the Rett syndrome gene, MECP2, causes x-linked mental retardation and progressive spasticity in males. American Journal of Human Genetics, 67, 982-985.
Meyer, K. A., Kennedy, C. H., Shukla, S., & Cushing, L. S. (1999). Receptive communication in late-stage Rett syndrome: A cautionary note. Journal of Autism and Developmental Disorders, 29(1), 93-94.
Meyer, L. H., Minondo, S., Fisher, M., Larson, M. J., Sunmore, S., Black, J. W., & D’Aquanni, M. (1998). Frames of friendship: Social relationships among adolescents with diverse abilities. In L. H. Meyer, H. S. Park, M. Grenot-Scheyer, I. S. Schwartz, & B. Harry (Eds.), Making Friends: The Influences of Culture and Development (pp. 189-221). Baltimore: Paul H. Brookes Publishing Co.
Moser, H. W. (1999). Dendritic anomalies in disorders associated with mental retardation. Developmental Neuropsychology, 16(3), 369-371.
Naidu, S. (1997). Rett syndrome: A disorder affecting early brain growth. Annals of Neurology, 42, 3-10.
Percy, A.K., Schultz, R., Glaze, D.G., Skender, M., del Junco, D., Waring, S.C., Zoghbi, H.Y., Jankovic, J.J., Williamson, W.D., & Stach, B.S. (1991). Trial of the opiate antagonist, naltrexone, in children with Rett syndrome. Annals of Neurology, 30, 486.
Perry, A., Sarlo-McGarvey, N., & Factor, D.C. (1992). Stress and family functioning in parents of girls with Rett syndrome. Journal of Autism and Developmental Disorders, 22(2), 235-248.
Perry, A., Sarlo-McGarvey, N., & Haddad, C. (1991). Brief reports: Cognitive and adaptive functioning in 28 girls with Rett syndrome. Journal of Autism and Developmental Disorders, 21, 551-556.
Piazza, C. C., Anderson, C., & Fisher, W. (1993). Teaching self-feeding skills to patients with Rett syndrome. Developmental Medicine and Child Neurology, 35, 991-996.
Plioplys, A. V. & Kasnicka, I. (1993). L-carnitine as a treatment
for Rett syndrome. Southern Medical Journal, 86, 1411-1413.
Riccardi, V.M. (1986). The rett syndrome: genetics and the future. American Journal of Medical Genetics, 24 (Suppl. 1), 389-402.
Sandberg, A. D., Ehlers, S., Hagberg, B., & Gillberg, C. (2000). The Rett syndrome complex: Communicative functions in relation to developmental level and autistic features. Autism: The International Journal of Research and Practice, 4(3), 249-267.
Schanen, N. C. (1999). Molecular approaches to the Rett
syndrome gene. Journal of Child Neurology, 14, 806-814.
Schilling, D. (1997). Our rett syndrome page. http://pages.prodigy.com/ DebbieSchilling.
Sekul, E.A., & Percy, A.K. (1992). Rett syndrome: clinical features, genetic considerations, and the search for a biological marker. Current Neurology, 12, 173-198.
Smith, T., Klevstrand, M., & Lovaas, O. I. (1995). Behavioral treatment of Rett’s disorder: Ineffectiveness in three cases. American Journal on Mental Retardation, 100 (3), 317-322.
Treffert, D. A. (1999). Pervasive developmental disorders. In, S. D. Netherton, D. Holmes, et al. (Eds.), Child and Adolescent Psychological Disorders: A Comprehensive Textbook. (pp. 76-97). New York: Oxford University Press.
Tsai, L.Y. (1992). Is rett syndrome a subtype of pervasive developmental disorders? Journal of Autism and Developmental Disorders, 22 (4), 551-561.
Van Acker, R. (1997). Rett syndrome: a pervasive developmental disorder. In, D. J. Cohen & F. R. Volkmar (Eds.), Handbook of Autism and Pervasive Developmental Disorders. (pp.60-93). New York: John Wiley & Sons, Inc.
Volkmar, F. R., Klin, A., Seigel, B., et al. (1994). Field trial for autistic disorder in DSM-IV. American Journal of Psychiatry, 151, 1361-7.
Volkmar, F. R. & Lord, C. (1998). Diagnosis and definition of autism and other pervasive developmental disorders. In F. R. Volkmar (Ed.) Autism and Pervasive Developmental Disorders. Cambridge: Cambridge University Press.
Volkmar, F. R. (1996). The disintegrative disorders: Childhood disintegrative disorder and Rett's disorder. In, F. R. Volkmar (Ed.), Psychoses and Pervasive Developmental Disorders in Childhood and Adolescence. (pp.223-248). Washington, DC: American Pychiatric Press, Inc.
von Tezchner, S., Jacobson, K. H., Smith, L., Skjeldal, A. H., Heiberg, A., & Fagon, J. F. (1996). Vision, cognition, and developmental characteristics of girls and women with Rett syndrome. Developmental Medicine and Child Neurology, 38, 212-225.
Wahlstrom, J., & Anvret, M. (1986). Chromosome findings in the rett syndrome and a test of a two-step mutation theory. American Journal of Medical Genetics, 24 (Suppl. 1), 361-368.
Wan, M., Lee, S. S., Zhang, X., Houwink-Manville, I., Song, H. R., Amir, R. E., Budden, S., Naidu, S., Pereira, J. L., Lo, I. F., Zoghbi, H. Y., Schanen, N. C., & Franke, U. (1999). Rett syndrome and beyond: Recurrent spontaneous and familial MECP2 mutations at CpG hotspots. American Journal of Human Genetics, 65(6), 1520-1529.
Witt-Engerstrom, I., & Gillberg, C. (1987). Rett syndrome in Sweden. Journal of Autism and Developmental Disorders, 17, 149-150.
Woodyatt, G. & Ozanne, A. (1992). Communication abilities and Rett Syndrome. Journal of Autism and Developmental Disorders, 22(2), 155-173.
World Health Organization (1993). Disorders of Psychological Development (Criteria for Research). Geneva: World Health Organization.
Zappella, M. (1990). A double-blind trial of bromocriptine in the Rett Syndrome. Brain and Development, 12, 148-150.
Zappella, M., Genazzani, A., Facchinetti, F., & Hayek, G. (1990). Bromocriptine in the Rett Syndrome. Brain and Development, 12, 221-225.
Zapella, M., Gillberg, C., & Ehlers, S. (1998). The preserved speech variant: A subgroup of the Rett complex: A clinical report of 30 cases. Journal of Autism and Developmental Disorders, 28(6), 519-526.
Zoghbi, H.Y. (1988). Genetic aspects of rett syndrome. Journal of Child Neurology, 3 (Suppl.), S76-S78.
Zoghbi, H.Y., Percy, A.K., Schultz, R.J., & Fill, C. (1990). Patterns of x chromosome activation in the rett syndrome. Brain and Development, 12, 131-135.
Zwaigenbaum, L. & Szatmari, P. (1999). Psychosocial characteristics
of children with pervasive developmental disorders. In, S. Schwean
& D. Saklofske (Eds.), Handbook of Psychosocial Characteristics of
Exceptional Children (pp. 275-298). New York: Plenum Publishers.
Return to Top