INTRODUCTION Rett syndrome (RS) is a
neurodevelopmental disorder that occurs almost
exclusively in females. It was described in 1966 by
Andreas Rett, an Austrian neuropediatrician.
Affected patients initially develop normally, then
gradually lose speech and purposeful hand use.
Deceleration of head growth, stereotypic hand
movements, seizures, autistic features, ataxia, and
breathing abnormalities subsequently develop. Most
cases result from mutations in the MECP2 gene.
EPIDEMIOLOGY In a report from a large
population-based registry in Texas, the prevalence
of classic RS was estimated as one per 22,800
females ages two through 18 years, or 0.44 per
10,000. Small geographic variations exist. The
prevalence per 10,000 girls was 0.56 in France, 0.65
in Sweden and Scotland and 0.72 in Australia. RS
occurs in all ethnic and racial groups, and at
GENETICS RS is caused by mutations in the
MECP2 gene, which maps to Xq28 and encodes
methyl-CpG binding protein 2 (MeCP2) . Although
MeCP2 is expressed in all tissues, it is most
abundant in the brain, which may be more sensitive
to abnormal MeCP2 than other tissues.
Three types of MECP2 mutations occur: missense,
frameshift, and nonsense. The type of mutation may
affect phenotypic expression. As examples, awake
respiratory dysfunction and lower levels of CSF
homovanillic acid (HVA) occurred more often with
truncating mutations, while scoliosis was more
common with missense mutations.
Most individuals with RS have random X-inactivation
(also known as lyonization) so that the normal
allele is expressed in some cells. The normal allele
appears to enable affected females to survive but
does not protect them from neurodevelopmental
abnormalities. Random inactivation also contributes
to the spectrum of phenotypes in RS. Except in
special circumstances such as Klinefelter syndrome
or mosaicism, similar mutations in brothers of
affected girls result in severe neonatal
encephalopathy and are lethal.
Some affected patients have nonrandom
X-inactivation. In one series, this was associated
with a milder phenotype or a mitigated classic RS
caused by a rare early truncating mutation.
Mutations in MECP2 have been detected in 25 to 100
percent of classic sporadic RS cases, 33 to 50
percent of atypical RS, and 0 to 30 percent of
familial cases. Variations in the rates of detected
mutations may relate to clinical criteria and
exclusion of variants, differences in testing
methodology, and abnormalities in noncoding or
promoter regions that have not been analyzed.
RS is sporadic in nearly all cases and is due to de
novo mutations in the MECP2 gene. These mutations
are almost exclusively of paternal origin. This may
explain the high female to male ratio in RS and
suggests another cause of male sparing besides
lethality. In familial cases, the mother was either
a carrier of the mutation, or a mosaic for the
mutation. In one family with affected male children
and a female child with classic RS, the MECP2
mutation was located on the mother's paternal
Mutations of the MECP2 gene have been detected in
other neurologic disorders. These include girls with
non-Rett phenotypes such as autism, girls and boys
with nonspecific X-linked mental retardation, and
boys with progressive spasticity, congenital
encephalopathy with respiratory arrest, or non-fatal
Mechanism How MECP2 mutations lead to Rett
syndrome is not yet established. MECP2 contains two
functional domains, a methyl-CpG binding domain and
a transcriptional repression domain. One possibility
is that interaction between these two domains leads
to transcriptional repression of some genes.
However, transcriptional profiling analyses have
failed to find consistent gene targets that are
silenced by MECP2.
Another possibility is that MECP2 normally functions
to repress transcription of some parentally
imprinted genes. MECP2 mutations might then cause a
loss of imprinting with subsequent target gene
dysregulation. Earlier reports that tested
well-established imprinted genes found no evidence
for loss of imprinting related to MECP2 mutations.
However, a later report found that MECP2 targeted
the DLX5 gene, a maternally imprinted gene on
chromosome 7q, and that MeCP2 was essential for the
organization of a higher order chromatin loop at the
DLX5-DLX6 locus that characterizes the silenced
status of DLX5. Increased expression of DLX5 (by a
factor of about two) was found in some brains of
individuals with Rett syndrome as well as in
MeCP2-null mice, supporting DLX5 dysregulation due
to loss of MeCP mediated imprinting.
DLX5 may function to induce expression of glutamic
acid decarboxlyase (GAD) and the differentiation of
gamma-amino butyric acid (GABA) producing neurons,
suggesting that alterations in GABAergic neurons may
be involved in the pathogenesis of Rett syndrome.
NEUROPATHOLOGY Brain growth is differentially
affected in RS. In a postmortem study of 39 patients
3 to 35 years old, most RS brains were smaller than
normal and did not grow after
age four years. In contrast, the heart,
kidneys, liver, and spleen grew at a normal rate
until 8 to 12 years of age. At that time, their
growth rate decelerated, but continued so that organ
weights were appropriate for height, which was also
reduced. Adrenal organ weights were normal.
Deceleration of brain growth in RS begins after
birth. The mechanism is uncertain but appear to
reflect arrested development. This is supported by
morphologic observations that include no evidence of
brain degeneration, no alteration in brain weight
with increasing age, lack of correlation of
dendritic length with increasing age, and reduced
neuromelanin in the substantia nigra.
In one study, the dendrites of pyramidal neurons
were examined in six regions of the cerebral cortex
in girls with RS, ages 2.9 to 35 years. The cortex
was selectively involved. The apical and basilar
dendritic branches in layers 3 and 5 of the frontal,
motor, and inferior temporal cortex were shorter
compared to brains in trisomy 21 or non-Rett
neurologic disorders. These findings did not change
In another report, the proteins that initiate
cortical dendritic differentiation and expansion
(Map2, adult form) and dendritic remodeling
(cyclooxygenase) were defectively expressed in RS.
This indicated marked disruption of a major
cytoskeletal component in the cortex. The
relationship of these findings with the MECP2
mutation is unknown.
Overview The clinical picture of RS is unique.
Affected patients initially develop normally, then
gradually lose speech and purposeful hand use.
Deceleration of head growth, seizures, autistic
features, ataxia, stereotypic hand movements, and
intermittent breathing abnormalities develop
Girls with classic RS are typically born at term
after an uneventful pregnancy and delivery. They
usually appear developmentally normal for at least
the first six months, although some are
retrospectively characterized as placid or slightly
floppy. Other nonspecific signs may be present
during the first six months, as illustrated by a
study in which videotapes of 22 Rett patients were
retrospectively reviewed. Detailed analysis revealed
abnormal quality of general movements, tongue
protrusion, postural stiffness, asymmetric eye
opening and closing, abnormal finger movements,
stereotyped hand and body movements, bursts of
abnormal facial expressions, and bizarre smile.
These observations further support earlier
observations that subtle developmental abnormalities
are present early, before regression. However, the
observations need to be confirmed by comparison to a
control group, such as siblings without a MECP2
Deceleration of head growth beginning as early as
two to three months is usually the first sign of RS.
At 12 to 18 months, loss of acquired fine motor,
intellectual, and communicative abilities is seen.
In some cases, this regression is rapid, with
parents reporting "She woke up and was no longer
speaking." In others, regression is slow and
insidious, occurring over weeks to months with loss
of interest in the surroundings and loss of
purposeful hand use. During this phase,
unprecipitated episodes of inconsolable screaming
may occur during the day or at night, disrupting
sleep. These begin abruptly and may last hours.
In the beginning of the regression phase,
stereotypic hand movements may be subtle and
interspersed with purposeful hand use. They
typically consist of periodic hand-to-mouth licking
or grasping of the hair or clothing. Each girl
develops her own distinctive unique hand pattern.
Some retain the ability to hold a cup or feed
themselves in a messy, rudimentary manner.
Following the regression phase, there is a period of
some recovery of nonverbal communication, with
improved eye contact and nonverbal interactions with
the environment. This is followed by a slow,
insidious deterioration in gross motor function.
Additional features that occur in the majority of
patients include: 1.Growth. 2.failure Epilepsy. 3.
Disorganized breathing pattern during wakefulness
characterized by periods of apnea alternating with
periods of hyperventilation. 4. Autonomic nervous
system dysfunction, characterized by cold feet and
peripheral vasomotor disturbances
Although cardiac abnormalities may predispose to
sudden death, lifespan in patients with Rett
syndrome appears to be unaffected. However, life
tables have not yet been established. Based on our
own experience of about 500 patients with Rett
syndrome, survival well into adulthood is typical.
Diagnostic categories The clinical phenotype
of RS is quite broad. Three diagnostic categories
have been proposed.
Classic Rett syndrome This group includes
individuals who meet all specific diagnostic
Provisional Rett syndrome This group
includes girls, typically one to three years old,
who have some clinical evidence of RS, but not
enough to meet all the specific diagnostic criteria.
Atypical Rett syndrome This group includes
girls with mental retardation of unknown etiology
who have at least three of six main criteria and
five of 11 supportive criteria and have none of the
exclusion criteria for classic RS. This category is
intended to account for the heterogeneous phenotypes
seen with MECP2 mutations, as well as atypical or
variant cases without the genetic abnormality.
STAGING A staging system is helpful to track
the clinical course of RS. It can be used as a tool
to anticipate potential clinical problems and
provide anticipatory guidance to parents. However,
it is often difficult to discern precisely
transitions between stages. In addition, this system
should not be used to predict life expectancy.
Stage I Stage I consists of developmental
arrest. The onset is between 6 to 18 months and it
may last for many months. During this time there is
less eye contact, reduced play, gross motor delays,
nonspecific hand wringing, and decelerating head
growth. Infants seem placid and not cuddly compared
to healthy infants.
Stage II Stage II consists of rapid
deterioration or regression. The onset is typically
between one to four years. It may be so acute that
parents can give a specific date after which their
child was no longer normal. In other cases, the
onset may be insidious. The duration is usually
weeks to months.
Stage II is characterized by the loss of purposeful
hand use and spoken language, and the onset during
wakefulness of hand stereotypes and periodic
breathing irregularities. Hand stereotypes are most
frequently midline and hand wringing or hand washing
in character, occur incessantly during wakefulness
but cease during sleep, and continue into adulthood.
During this stage, many affected girls exhibit
autistic-like behavior. Many experience variable
periods of unprovoked inconsolable crying or
irritability and a disturbed sleep pattern.
Stage III Stage III is the pseudostationary
stage. It begins at 2 to 10 years of age, following
the period of rapid deterioration. This stage lasts
many years and is characterized by behavioral
improvement and some improvement in hand use and
communication skills, particularly by using
eye-pointing. Motor dysfunction and seizures are
more prominent during this stage.
Stage IV Stage IV consists of late motor
deterioration and usually begins after 10 years of
age. It is characterized by increased rigidity and
reduced mobility, dystonia, hypomimia, and
bradykinesia. Stage IV is further divided into stage
IVA (previously ambulant) and Stage IVB (never
ambulant). Cognitive function is stable and
interpersonal communication may continue to improve.
However, spoken communication is not regained.
Seizures also often improve. Quadriparesis,
scoliosis, and staring may be features of this
Differential diagnosis Depending upon the
stage of presentation, alternative disorders should
be considered. The differential diagnosis for each
stage includes the following conditions: Stage I
Benign congenital hypotonia, Prader-Willi syndrome,
and cerebral palsy Stage II Autism, hearing/visual
disturbance, encephalitis, and metabolic or
degenerative disorders such as neuronal-ceroid
lipofuscinosis, phenylketonuria, and urea cycle
disorders. Stage III Spastic ataxia, cerebral
palsy, spinocerebellar degeneration,
leukodystrophies, neuroaxonal dystrophy,
Lennox-Gastaut syndrome, and Angelman syndrome Stage
IV Unknown degenerative disorder
DIAGNOSIS The diagnosis of RS is based upon
clinical characteristics. Affected children should
meet all necessary criteria, demonstrate some or
many of the supportive criteria, and have none of
the criteria for exclusion. Detection of mutations
in the MECP2 gene may be helpful. However, this
abnormality is not present in all cases.
Diagnosis of RS in middle childhood is usually
straightforward because of the distinctive
presentation. However, diagnosis in early infancy
may be more difficult. In the absence of the MECP2
mutation, the diagnosis cannot be made definitively
in the young child with decreasing head growth and
delayed gross motor skills until she reaches the
regression phase and shows other characteristic
features of RS. The diagnosis can usually be made in
an adult mentally retarded woman with typical signs,
including the prominence of motor problems with
progression from a hyperkinetic to a bradykinetic
state, and lower motor neuron features.
History A thorough history should be obtained
from the parents. Special attention should be paid
to the timing of developmental milestones and the
presence of abnormal hand movements.
Physical examination Physical examination
should identify the characteristic findings of RS.
Measurements typically show impaired growth,
especially of head circumference. A variety of
neurologic manifestations may be seen, including
mental retardation or developmental delay, loss of
or poor communication skills, and stereotypic hand
DNA analysis A blood sample should be obtained
for DNA analysis to identify mutations of MECP2 in a
female with characteristic signs. Testing should
also be considered in male infants with severe
encephalopathy. The diagnosis of RS (MECP2 positive)
is made if the MECP2 mutation is found and clinical
criteria are met.
To avoid unnecessary and expensive DNA testing, a
screening checklist for RS has been proposed. The
checklist is based upon the necessary criteria for
the diagnosis of RS and assigns points for
individual items. A total score 8 had a specificity
of 100 percent and eliminated from genetic testing
nearly one-half of the girls without mutations. Use
of this checklist may be appropriate in girls over
two years old. However, because the full profile of
RS may not be developed in younger girls, screening
with the checklist may delay diagnosis. For example,
we have identified girls at one year of age with
MECP2 mutations who presented with mild
developmental delay and deceleration of head growth
without other criteria for RS.
Other studies If no mutations of MECP2 are
identified, other inborn errors of metabolism and
neurodegenerative disorders should be considered.
The following studies should be performed: 1. Brain
MRI. 2.Serum amino acids. 3.Urine organic acids.
4.Chromosome analysis, with specific attention to
Chromosome 15, and FISH for Angelman Syndrome.
5.Hearing test. 6.Ophthalmologic evaluation
If these studies are
nondiagnostic and clinical criteria are met for RS,
the patient is considered to have RS without the
Electroencephalogram The electroencephalogram
(EEG) may be helpful in the evaluation of RS,
although it is not used for diagnosis. The EEG is
always abnormal and shows characteristic changes.
The epileptiform abnormalities typically begin at
approximately two years of age. The EEG subsequently
deteriorates, with loss of expected developmental
features and the appearance of abnormal patterns.
These include focal, multifocal, and generalized
epileptiform abnormalities, and the occurrence of
rhythmic slow (theta) activity primarily in the
Evoked potentials typically demonstrate intact
peripheral auditory and visual pathways and suggest
dysfunction of central or higher cortical pathways.
Somatosensory evoked potentials may be characterized
by "giant" responses suggesting cortical
ASSOCIATED CONDITIONS Patients with RS often
have serious medical conditions associated with the
disorder. These include growth failure, seizures,
cardiac abnormalities that may lead to sudden death,
motor dysfunction, scoliosis, breathing dysfunction,
and sleep disturbance.
Growth failure The characteristic growth
pattern of RS consists of early deceleration of head
growth, followed by deceleration of weight and
height measurements. This pattern deviates from
growth aberrations associated with chronic disease
or central nervous system or chromosomal disorders
and is similar to patterns seen with acute and
chronic malnutrition. It may provide the earliest
clinical indicator for the diagnosis of RS.
Characteristic patterns were identified in a
longitudinal study of growth in 96 affected girls.
The following findings were noted: Median head
circumference followed the 50th percentile from
birth to three months. The rate of head growth then
decelerated and head circumference fell below the
2nd percentile by four years. Median length
approximated the NCHS 50th percentile until 16
months, then gradually deviated to the 5th
percentile by seven years. Median weight deviated
from the NCHS 50th percentile after age four months
and crossed the 5th percentile at age four years.
Deviation below the 5th percentile increased with
advancing age for both weight and height. The mean
height-for-age Z score was -4.0 SDs by age 16 years,
and the mean weight-for-age Z score was -4.0 SDs at
age 18 years. In another study, girls with RS had
slower rates of hand and foot growth than normals.
Relative to height, the rate of decelerated growth
was greater for feet than hands.
Nutrition Although multiple factors are likely
responsible for the growth aberration in RS,
inadequate nutrition appears to play an important
role. This may result from inadequate dietary
intake, increased energy expenditure, and/or feeding
The contribution of increased energy expenditure due
to involuntary repetitive movements is uncertain. In
one study, total daily energy expenditure (TDEE)
adjusted for differences in body weight was similar
in RS and healthy girls. In another study from the
same group, metabolic rates while sleeping and
quietly awake were 23 percent lower in RS girls than
controls; rates while actively awake were similar.
Although TDEE was similar in the two groups, energy
balance was less positive in the RS girls than
controls. If sustained, these small deficits in
energy balance may account for growth failure.
Aggressive nutritional support improves growth in
RS, confirming the importance of dietary energy
intake. In a preliminary report, an aggressive
nutritional intervention was made in RS girls using
gastrostomy feedings in amounts that approximated an
energy intake of 85 kcal/kg per day. During one
year, the velocity for height and weight increased
by 33 percent and tenfold, respectively. However,
the weight gain consisted of 63 percent fat and only
37 percent lean body mass. This deficit in lean body
mass deposition may be explained by a defect in body
protein metabolism. In another preliminary report,
rates of amino acid loss were significantly greater
in RS than controls, indicating failure to suppress
endogenous body protein degradation.
Feeding impairment Feeding impairment,
characterized as chewing or swallowing difficulties,
choking, and nasal regurgitation, frequently
complicates RS. In addition to oromotor dysfunction,
the upper gastrointestinal (UGI) tract may be
affected. In a study of 34 RS females age 2.3 to
40.1 years, oropharyngeal dysfunction and UGI
dysmotility occurred in 95 and 68 percent,
respectively. Abnormalities of oropharyngeal
function included poor tongue mobility, reduced
oropharyngeal clearance, and laryngeal penetration
of liquids and solid foods during swallowing.
Esophageal dysmotility, characterized by the absence
of primary or secondary waves, delayed emptying,
atony, the presence of tertiary waves, or spasm was
found in 11 patients (39 percent). Gastroesophageal
reflux (GER) was present in 11 patients (35
percent), including one with nasopharyngeal reflux.
Six patients (20 percent) had gastric dysmotility,
characterized as decreased peristalsis or atony, and
one had duodenal dysmotility. In another study,
decreased dietary energy intake was associated with
poor chewing and persistence of liquid and solid
food residue in the pyriform sinuses and valleculae,
as well as decreased body fat.
Bone mineral deficit Bone density frequently
appears diminished on conventional radiographs in RS
girls, although the cause is unknown. This is seen
in affected children (age two to five years) and
adults, whether or not they are ambulatory. RS girls
have abnormally low regional bone mineral density
and whole-body bone mineral content. In one study,
bone mineral content was measured by dual-energy
X-ray absorptiometry in six RS girls (age 7 to 12
years); children with cystic fibrosis, juvenile
dermatomyositis, liver disease, and human
immunodeficiency virus; and healthy controls. Bone
mineral deficit was greatest in the RS patients, who
all had severe abnormalities (osteoporosis).
Seizures Seizures occur in the majority of RS
patients. In a series of affected females in West
Sweden diagnosed between 1971 and 1998, 50 of 54 (94
percent) had epilepsy. Only five patients were
seizure-free for more than five consecutive years
and three never had seizures. Two of the nine deaths
that occurred were associated with seizures
(aspiration and status epilepticus). Patients in the
Swedish series had all seizure types except for
typical absences and clonic seizures. The most
common types were complex partial, tonic-clonic,
tonic, and myoclonic seizures. Seizures were
controlled with antiepileptic medication in 46
percent, while the remainder of patients had
intractable epilepsy. The latter was associated with
smaller head circumference. Status epilepticus
occurred in 19 of 50 patients-38 percent.
The median age at seizure onset was four years, with
a range of 0.2 to 27.6 years. Onset before one year
of age was associated with more severe epilepsy,
including more seizure types, more frequent
intractable epilepsy, and status epilepticus. Early
seizure onset was more likely to be associated with
an atypical or variant form of RS. In another
report, 6 of 94 RS females had onset of epilepsy in
infancy. In all, intractable seizures preceded the
appearance of classic RS features. The occurrence of
epilepsy may be overestimated because affected
patients have a variety of abnormal behaviors that
may be reported as seizure manifestations. These
include breath holding, hyperventilation, incessant
hand wringing, "vacant" episodes with
sudden-absence-like freezing of activity,
inappropriate screaming or laughter, and motor
abnormalities (dystonia, tremulousness, and
limpness). However, these events may not have
associated EEG changes. This was illustrated by a
study of video/polygraphic/EEG monitoring in 82 RS
females age 2 to 30 years, all of whom had
epileptiform abnormalities on EEG. During
monitoring, 51 percent of the parents identified
events that they thought represented their child's
typical seizure, such as twitching, jerking, head
turning, falling forward, and trembling, as well as
episodes of staring, laughing, pupil dilatation,
breath holding and hyperventilation. However, only
18 percent of these clinical episodes correlated
with an EEG seizure discharge. In addition, some
actual seizures were unrecognized by parents or
occurred during sleep.
Cardiac abnormalities The incidence of sudden,
unexpected death is higher in RS than the general
population (22 to 26 versus 2.3 percent). The
mechanism is thought to be cardiac electrical
instability due to abnormal autonomic nervous system
regulation. Increased sympathetic activity is
suggested by the increased incidence of prolonged
QTc in RS. In several reports, the incidence of
prolonged QTc (>0.45 msec) was higher and heart rate
variability was lower in girls with RS than
age-matched healthy girls. An increased proportion
of QTc interval prolongations with advancing RS
clinical stage has been shown by some studies but
not by others.
Abnormal autonomic regulation was also suggested by
a study of cardiac vagal tone, cardiac response to
baroreflex, and beat-to-beat heart rate measured
during rest, hyperventilation, and immediately after
hyperventilation in RS girls. A deficiency in
substance P in the central nervous system identified
in RS girls may contribute to impairment of
autonomic nervous system dysfunction, resulting in
Approximately 50 to 70 percent of RS patients have
clinical features that indicate autonomic nervous
system dysfunction with increased sympathetic tone.
These include the presence of cold, blue feet and/or
hands, drooling, and breathing irregularities. A
report of the relief of the vasomotor instability in
the ipsilateral foot after an inadvertent unilateral
sympathectomy during scoliosis surgery in an RS
patient also suggests that sympathetic tone was
Motor dysfunction Extrapyramidal motor
dysfunction with stereotypic hand movements and gait
disturbance affects all RS patients. Stereotypic
hand movements include opposition of hands, finger
kneading and rubbing, hand clapping and washing,
wringing, squeezing, twisting, and pill rolling. The
gait typically is broadbased, clumsy, and
ataxic/apraxic. Patients often have retropulsion and
rock to and fro while standing or sitting. Many have
difficulty crossing from one floor surface or color
to another and will stop and refuse to take another
Extrapyramidal motor disturbances were
characterized in a series of 32 affected patients,
age 30 months to 28 years. Abnormalities identified
in addition to stereotypic movements and gait
disturbance included: Bruxism 97 percent.
Oculogyric crises 63 percent. Dystonia 59
percent. Proximal myoclonus 34 percent. Excessive
drooling 75 percent. Rigidity 44 percent.
Bradykinesia 41 percent. Hypomimia 63 percent.
The underlying mechanism for these extrapyramidal
disturbances is not known.
Scoliosis Scoliosis that is neurogenic
develops in 50 to 70 percent of RS patients. Factors
influencing the onset of spinal curvature include
postural alignment, gradual loss of equilibrium
responses, loss of spatial perceptual orientation,
loss of transitional motor skills, and onset of
Scoliosis typically presents between 8 to 11 years
of age and may progress rapidly. In a Swedish series
of 106 patients age 1 to 54 years, scoliosis was
identified before 11 years in 40 percent, with 14
percent before five years. The range of curvature
was wide and progressed with age in the majority.
However, curvature remained unchanged in 17 percent.
The likelihood of progression and worsening appears
to be greater in patients with early hypotonia,
dystonia, or loss of ambulation. Kyphosis occurs in
some RS patients and may require surgical
Breathing dysfunction A characteristic pattern
of disordered breathing during wakefulness occurs in
60 to 77 percent of RS patients. This pattern
consists of episodes of hyperventilation with
concomitant hypocapnia alternating with
hypoventilation and/or apnea. The periods of
hypoventilation and/or apnea may last as long as 20
to 120 seconds and result in hypoxemia. Breathing
usually is normal between these episodes.
Episodes of hyperventilation tend to occur when the
child is excited or agitated, and are frequently
associated with other stereotypic movements. Apnea
that occurs during wakefulness is typically central,
although it may be obstructive. These events may be
isolated, or precede or follow hyperventilation.
During apneic episodes, the child may stare quietly
ahead or smile and appear happy with no evidence of
distress, despite severe cyanosis. Apnea may occur
in inspiration or expiration. In one study using
fiber optic endoscopy significant oxygen
desaturation occurred in expiration but not
Breathing abnormalities may cause severe hypoxemia.
In studies recording EEG and breathing in our
laboratory, hypoxemia led to electrographic seizures
only when it was associated with apnea. Seizures did
not occur with disorganized breathing alone, even
when oxygen saturation was as low as 30 to 50
percent. The awake breathing abnormalities are not
associated with bradycardia.
The breathing pattern during wakefulness does not
appear to be related to the RS stage. The most
severe desaturations typically appear in Stage III;
these may decrease in frequency and severity during
Stage IV. The underlying pathophysiology and
relationship to the MECP2 mutation are unknown. It
has been suggested that the disordered breathing may
be due to an abnormality of cortical influences on
ventilation or awake control of breathing, rather
than brain stem control of ventilation.
Breathing typically is normal during sleep. However,
some reports note increased periodic breathing
during sleep or central apnea of 20 seconds or
greater during REM sleep.
Sleep disturbance Sleep disturbances affect
approximately 57 to 80 percent of RS patients and
are a problem for both the patient and her
caregivers. The symptoms most commonly reported by
caregivers are irregular sleep times, including
prolonged periods of wakefulness or sleep, periodic
nighttime awakenings with disruptive behavior (such
as crying, screaming, laughing), and abbreviated
total nighttime sleep with increased amounts of
daytime sleep. Sleep architecture is abnormal in RS.
In one report, the amount of REM sleep was less than
age-matched healthy controls.
MANAGEMENT No specific therapy is available
for RS. Management consists of treating the
associated conditions. A multidisciplinary approach
The first important step in management is confirming
the diagnosis of RS. This is often a relief to
families who have searched for an explanation of
their child's problems. It may also be the beginning
of the grief process for the loss of a normal child.
At the time of diagnosis, anticipatory guidance
should be provided regarding the spectrum of
clinical problems. All parents should be taught
C Genetic testing DNA analysis should be
offered to the female siblings of RS patients with a
mutation in MECP2 and to the mother if future
pregnancies are planned. Male siblings with
neurologic or developmental disorders should also be
tested. Prenatal testing is available.
Nutrition Somatic growth should be closely
monitored. A high calorie, well-balanced diet should
be provided with vitamins and minerals at the
recommended dietary allowance. If needed to maintain
adequate growth, energy intake should be increased
with high-calorie supplements either orally or by
GI dysfunction Oromotor function should be
assessed by videofluoroscopy in children who have
choking, decreased control of secretions, frequent
upper or lower respiratory infections, or weight
loss. An individualized treatment plan should be
developed including appropriate food and beverage
consistencies, positioning, and the use of selected
feeding utensils. Patients with a history of eating
difficulty, eructation, emesis, or irritability
should be evaluated for possible GER.
Constipation can be a severe and chronic problem for
many patients. One approach is a program of daily
prophylaxis. Options include Miralax 1 cap (3 tsp)
dissolved in 4 to 6 oz of water, juice, or milk
daily with titration up or down by 0.5 tsp, or Milk
of Magnesia 0.5 to 1.0 cc/kg per day as a single
dose daily with titration up or down by 2.5 cc.
Bone mineral deficit Severe bone mineral
deficit (osteoporosis) is common and may lead to
fractures. Affected patients with crying and/or
screaming episodes of unknown etiology should be
evaluated for fractures.
Seizures Seizures may occur during sleep or
not be recognized by caregivers. Conversely, many
behavioral events identified by parents as seizures
are nonepileptic. Thus, video-EEG monitoring may be
necessary to differentiate nonepileptic behavioral
events from actual seizures and to identify
Most seizures are easily controlled and respond to
standard antiepileptic drugs. A ketogenic diet or
vagus nerve stimulator may improve intractable
seizures. However, in view of the frequent
occurrence of growth failure, a ketogenic diet
should be used with caution. Hormonal therapy may be
helpful in patients with infantile spasms.
Breathing dysfunction There is no known
treatment for apnea during wakefulness. In our
experience, treatment with supplemental oxygen or
rebreathing has not resulted in improvement;
rebreathing has occasionally worsened the apnea.
Naltrexone and magnesium citrate have been reported
to lessen the severity of disordered breathing. In
our experience, these have been beneficial to a
small number of girls. A preliminary report
suggested that parenteral naloxone might be helpful
for disordered breathing. However, a controlled
trial of oral naltrexone failed to show benefit.
Apnea during sleep is not characteristic of RS. It
should be evaluated as in any patient with sleep
Cardiac abnormalities An ECG should be
obtained when the diagnosis of RS is made. If the
QTc > 0.45, a cardiologist should be consulted. The
ECG should be monitored annually. The family history
should be reviewed for sudden unexpected death. In
some cases, it may be appropriate to obtain an ECG
on the parents.
Medications associated with prolongation of the QT
interval (eg, tricyclic antidepressants,
erythromycin) should be avoided. Beta blockers such
as propranolol may be appropriate in some cases.
Scoliosis Scoliosis should be identified as
early as possible with serial examinations at yearly
intervals, or more often if rapidly changing.
Optimal treatment for scoliosis in RS is not
certain. Bracing to control progression of the
curvature does not appear to be helpful. Early
referral to an orthopedic surgeon and aggressive
surgical management are recommended.
Sleep disturbance Evaluation of sleep
disturbance should include characterization of night
and daytime routines, time of occurrence and related
factors, and impact on the family as a whole.
Specific disorders that disturb sleep should be
considered, such as sleep apnea secondary to
tonsillar and/or adenoidal hypertrophy,
gastroesophageal reflux, and seizures.
Behavioral intervention should be attempted to treat
dysfunctional sleep patterns. Good sleep habits
should be encouraged, including the maintenance of
regular day and night routines and allowing the
child only to sleep in bed. This approach includes
establishing a bedtime conducive to rapid sleep
onset, removing the child from the bed if she does
not fall asleep within one hour, and avoiding
daytime sleep except for scheduled naps. Other
measures that may be helpful are taking a warm bath
one to two hours before sleep, avoiding caffeine,
exercising no later than three to four hours before
bedtime, and following a routine bedtime ritual.
Bright light exposure in the early morning promotes
early sleep time, while evening exposure promotes
later sleep time and should be avoided.
Pharmacological agents are not consistently
successful at correcting sleep disorders. Many
disrupt the normal sleep architecture and/or have
persistent effects on the following day. Alternative
therapies may include short-acting,
non-benzodiazepine receptor agonists (such as
zaleplon or zolpidem). Melatonin has improved sleep
disturbances in some RS patients, but further
studies are needed before it can be recommended.
Motor dysfunction A program of physical,
occupational, and communication therapy should be
provided. Physical therapy is thought to promote
ambulation and balance, prevent or retard the
development of contractures, and control
The goal of occupational therapy is to promote
purposeful use of the hands. Hand stereotypies can
often be diminished by providing elbow or hand
restraints. It may only be necessary to restrain the
non-dominant hand or elbow. In several small series,
splinting to inhibit repetitive hand activity was
associated with improvements such as increased
socialization and interaction with the environment.
Therapy should be provided to enhance communication
skills. The majority of girls with RS lose
expressive language, although some may retain
one-word expressions. They usually communicate via
eye gaze, body language, and facial expressions.
Parents and educators must attune themselves to
their child's communicative behavior and respond
consistently to these signals. A computer-based
requesting system may be an effective communication
Other types of therapy may be helpful, although
little data are available to support their use.
Music therapy may facilitate sustained focus,
attention, and improve interaction. Hydrotherapy may
promote movement and balance. Horseback riding may
promote balance and protective responses that help
maintain mobility and avert falls.
Reproductive issues Girls with RS go through
puberty, menstruate, and may become pregnant. Issues
and options concerning birth control and hygiene
should be discussed with parents or guardians of
women with RS.