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
Symptoms
Epidemiology
Etiology
Assessment
Treatment
Author
Shane R. Jimerson, Mendy Boettcher, Catherine M. Brown, and Monette
Tijerina
University of California, Santa Barbara
Rett Syndrome
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.
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
3) Seizures
4) Muscle rigidity/spasticity/joint contractures
5) Scoliosis
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.
EPIDEMIOLOGY
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.
ETIOLOGY
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.
I. ASSESSMENT
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.
TREATMENT
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.
II. WEBPAGES
The Australian Rett Syndrome Homepage. Caratine as a Treatment
for Rett Syndrome.
http://www.general.uwa.edu.au/uhleonard/rett.html
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
Center: http://www.bcm.tmc.edu/neurol/index.html
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:
http://www3.ncbi.nlm.nih.gov/htbin-post/Omim/dispmim?312750
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
Information): http://www3.ncbi.nlm.nih.gov/Omim/
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:
http://www.rettsyndrome.org/rebecca_hulst/
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.
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