Talking psychiatry...Rett syndrome

INDEX

 INTRODUCTION

INTRODUCTION

Rett syndrome is a relatively rare neurodevelopmental disorder (incidence: approximately one out of
10,000 female births) that reached worldwide prominence in the early 1980s. Owing to its overwhelming
predominance in females, Rett syndrome was regarded as a genetic disorder. However, its occurrence is
sporadic, with a recurrence risk well below 0.5%. In 1999, confirmation was provided by the
demonstration of mutations in the MECP2 gene. At present, more than 95% of females who fulfill
consensus criteria for Rett syndrome have a mutation in this gene. Over the past 25 years, understanding of
the clinical features and natural history of this unique neurodevelopmental disorder has evolved
dramatically. However, large segments of healthcare professionals and the general public still remain
relatively uninformed. This review details the clinical picture of Rett syndrome and the diagnostic
strategies required, explores the critical medical issues and recent advances in molecular neurobiology,
provides an overview of intervention strategies that have been developed to date and sets the stage for

future treatment trials as novel, and potentially effective, pharmacologic or molecular interventions
become available.

Physicians and related healthcare professionals, basic scientists and educators are, generally, uninformed
about Rett syndrome (RS). Indeed, RS is a relative newcomer to the field of neurodevelopmental disorders.
Despite being one of the 'new kids on the block', significant advances have emerged in recent years
regarding our understanding of the clinical features, molecular genetics and neurobiology of RS,
particularly following the recognition that mutations in the gene, MECP2, are responsible. In the absence
of a fundamental therapy, serious energies have been directed to developing rational intervention
strategies. Excitement was generated within the past year by the potential for reversing the devastating
consequences of RS.[1,2] Through molecular manipulation, a mouse model for RS was engineered to allow
activation of Mecp2 once the mice had developed the clinical phenotype associated with absence of this
gene. At the same time, studies in another mouse model provided important new information on the
molecular neurobiology of RS.[3,4] These studies allowed the authors to suggest a neuroendocrine
component involving elevated corticotrophinreleasing hormone (Crh) and elevated corticosterone levels
(cortisol in humans) in the pathobiology of this disorder. Taken together, the findings support the notion
that the clinical features of RS could be modified by appropriate interventions and suggest at least one
potential avenue for doing so. This review provides background information on RS, including diagnosis,
medical issues, genetics and molecular neurobiology, and explores potential therapeutic strategies.

 History

Rett syndrome is a relatively rare neurodevelopmental disorder found almost exclusively in females. RS
was recognized independently in the early 1960s by two European physicians, Andreas Rett in Vienna and
Bengt Hagberg in Gothenborg, Sweden. However, widespread prominence was not achieved until 1983
following a chance meeting between them, which generated the first widely read description.[5] Within a
short time, RS was diagnosed throughout the USA and the International Rett Syndrome Association
(IRSA) was formed, becoming the information clearing house in this country and, to some extent,
worldwide. RS has been identified across the world in all racial and ethnic groups with an incidence
approximating one in 10,000 females.[6] In the 1980s, RS was already presumed to be X linked, based on
almost total occurrence in females, twin studies and vertical transmission from an affected woman to her
female offspring.[5] Detailed molecular studies taking advantage of an X chromosome–autosome
translocation in one girl with RS,[7] and several instances of familial recurrence[8,9] restricted the X-
chromosome target area to Xq28, a gene-rich region where MECP2 resides. In 1999, the identification of
mutations in MECP2 confirmed its genetic basis.[10] Nonetheless, RS is generally not transmitted from
generation to generation but is sporadic: the recurrence risk is well below 0.5%. At present, more than
95% of females who fulfill consensus criteria for RS have a MECP2 mutation.[11] In the North American
databases, 91% of females who met consensus criteria for RS and who had MECP2 testing had a mutation.
[12] This number is lower because testing for large deletions was not conducted routinely in this cohort.

 Diagnosis

The diagnosis of RS is based on recently refined consensus diagnostic criteria.[13] These criteria provide
the basis for standardized clinical diagnosis of RS throughout the world ( Box 1 ). Approximately 85% of
females with RS will fulfill these criteria. The remaining 15% have one of several variant forms for which
diagnostic criteria have also been elaborated ( Box 2 ).[13] These variants include an early-onset seizure
type, a congenital form lacking normal early development, a preserved speech variant with some
purposeful language, and a delayed form or forme fruste. Children who fulfill diagnostic criteria, whether
typical or variant, should be tested for mutations in MECP2. This would include young females (624
months) who display only some features associated with RS, such as low muscle tone, deceleration in the
rate of head growth or unexplained developmental delay or frank regression. With the advent of effective
treatment strategies, early diagnosis prior to full expression of typical features will be crucial. Individuals
meeting consensus criteria, of whom 95% or more will have a mutation,[12] should have molecular genetic
testing for mutations in MECP2. Such testing should include sequencing of the four exons associated with

this gene, as well as testing for large-scale deletions in those individuals who have negative results by
standard sequencing analyses. For those mutations identified by sequencing, the vast majority will occur in
exons 3 and 4. Of the individuals meeting variant criteria, 55-60% will have a mutation.[12] It is critical
that healthcare providers be aware that sequencing and large deletion testing involve different
methodologies. Analyses for large deletions should be requested whenever sequencing fails to identify a
mutation.

Box 1. Consensus Criteria: Typical Rett Syndrome

 Normal prenatal and perinatal periods

 Normal at birth and apparently normal early development (may be delayed at birth)
 Postnatal deceleration of head growth in most cases
 Lack of achieved, purposeful hand skills
 Psychomotor regression: emerging social withdrawal, communication dysfunction, loss of learned words,
and cognitive impairment
 Stereotypic movements during wakefulness: hand washing/wringing/squeezing/clapping/tapping/rubbing,
hand mouthing; finger rubbing
 Gait dysfunction: impaired (dyspraxic) or failing locomotion

Box 2. Consensus Criteria: Typical Rett Syndrome

Main criteria (must fulfill at least three out of the six main criteria):

 Absence or reduction of hand skills

 Reduction or loss of babble speech
 Reduction or loss of communication skills
 Deceleration of head growth from the first years of life
 Monotonous pattern of hand stereotypies
 Rett syndrome disease profile: regression stage followed by recovery of interaction contrasting with slow
neuromotor regression

Supportive criteria (must fulfill at least five out of the 11 supportive criteria):

 Breathing irregularities

 Bloating/air swallowing
 Bruxism (harsh sound)
 Abnormal locomotion
 Scoliosis/kyphosis
 Lower limb amyotrophy
 Intense contact/eye pointing
 Diminished response to pain
 Laughing/screaming spells
 Cold, purplish feet, usually growth impaired
 Sleep disturbances, including night screaming outbursts

MECP2 testing should also be requested for females who demonstrate the characteristics of Angelman
syndrome but have normal methylation or mutation studies at the Angelman locus. Males with features of
RS or with X-linked mental retardation and normal Fragile X testing, and infants with unexplained
neonatal or infantile encephalopathy, should also be tested.[14] Recently, males with cognitive delay, little

or no speech and an unusual gait, with or without recurrent upper respiratory infections, have been
described in association with duplications of MECP2.[15-20] These individuals should have
deletion/duplication or comparative genomic hybridization (CGH) array testing.[19]

MECP2 testing is available in a number of different clinical laboratories throughout the world. In the USA,
these include the Baylor College of Medicine in Houston (TX) and the Greenwood Genetic Center in
Greenwood (SC).

 Genetics

More than 95% of females fulfilling criteria for RS have a MECP2 mutation.[11] More than 200 distinct
mutations have been identified, but eight common mutations (four nonsense and four missense mutations)
account for most individuals with RS. In the recently published North American database[12] and in the
International Rett Syndrome Association-funded Australian RettBase, the four most common mutations
are T158M, R168X, R255X and R270X. Missense mutations represent 39.0%, nonsense mutations 35.2%,
large deletions 6.4% and C-terminal truncations 8.8% of the total mutations in the North American cohort.
As stated previously, the number of large deletions is likely to be under-represented in this cohort because
of incomplete testing in some females, especially those diagnosed prior to 2000.

Phenotypic variability may be striking.[12] Females with such mutations may be completely normal or
have clinical features ranging from mild learning disabilities, to Angelman syndrome, to autism and to RS.
Females who appear normal or have learning disabilities generally share the same mutation as a sibling or
child with RS, but lack features of RS owing to favorable skewing of X-chromosome inactivation. Females
with features of Angelman syndrome represent the close clinical overlap during early childhood between
the two disorders, and females who have autism but not RS reflect either favorable skewing in X -
chromosome inactivation or less severe mutations.

Rett syndrome has been identified in males who have an extra X chromosome (Klinefelter syndrome)[21]
and in males with somatic mosaicism, some cells expressing normal X chromosomes and others expressing
MECP2 mutation-bearing X chromosomes.[22] These males resemble females with balanced X-
chromosome inactivation. Most males with MECP2 mutations display a much more severe progressive
encephalopathy with motor and respiratory problems present from birth orearly infancy and premature
death often by 1-2 years. Approximately 50% have the same mutation as an affected sibling(s), whereas
others represent sporadic occurrences.[14,15] Still, other males demonstrate only X-linked mental
retardation. A majority of these males will have a duplication of the Xq28 locus including MECP2. Based
on the numbers presently reported, this MECP2 duplication disorder is likely to be the most common
finding in males associated with MECP2 mutations or extra copy number.[15-20]

 Phenotype-genotype Correlations

Clinical severity does depend on mutation type and position. A number of reports have appeared in recent
years dealing with the relationships between the clinical picture and the specific MECP2 mutation. Over
time, these analyses have been derived from increasingly larger datasets and, hence, provided greater
reliability. In general, mutations more distal in the gene, such as R294X, R306C and C-terminal
truncations, produce milder involvement.[23] However, strikingly milder features have also been
associated with the R133C mutation that is much more proximal in the gene. Two papers in Neurology
support these findings and provide the most extensive published information to date.[11,24] The largest
longitudinal dataset is currently held with the NIH-sponsored Rare Disease Clinical Research Network
data repository. Preliminary analyses of data from more than 400 participants substantiate the general
conclusions noted previously.[25] Any conclusions derived solely from mutation type and position will most
probably be affected by other factors, the most prominent being imbalances in X-chromosome inactivation
or differences in the specific neuronal po-pulations impacted by an abnormal MECP2.

 Clinical Picture

Rett syndrome typically becomes evident between 6 and 18 months of age. Before then, most parents report
normal pregnancy, birth and early motor and social development, but the infants are, perhaps, 'too good'.
Early development may not be normal, but this is often difficult for parents to discern. Single words or
phrases often appear. However, hypotonia or reduced muscle tone is commonly noted during this early
period, and growth patterns are often problematic, including deceleration in the rate of head growth (as
early as 3 months of age) and poor weight gain. It should be emphasized that deceleration in the rate of
head growth does not necessarily mean microcephaly. Many of these children have head circumferences in
the normal range, while in approximately 50% head circumferences decline into the microcephalic range.
Indeed, a small number may demonstrate no decline in head circumference growth rate at all, despite
having the other features of RS. Deceleration in the rate of linear growth typically follows the first
birthday.[26] The first abnormal clinical signs may include increasing irritability with inconsolable crying
and stagnation or plateauing in motor development, ultimately leading to frank regression and virtual loss
of fine motor skills. It is during this period that autistic-like behavior appears, as contact with others
diminishes or is lost. Other communication elements may also be lost, with some appearing as if they do not
hear despite normal hearing assessments. Persistent stereotypic hand movements, noted only while awake,
emerge during or shortly after this regression period. These may consist of hand-wringing, -patting, -
clasping, -squeezing, or mouthing, picking at the clothes or skin, or twirling their hair. Generally, but not
always, the hands are held in the midline. Each girl will have her own repertoire of stereotypies that
continue to evolve over time. The hand stereotypies often dominate waking moments and tend to be
exacerbated by stress or excitement.

Approximately 80% develop independent ambulation. However, the gait is dyspraxic and nonpurposeful,
generally on a wide base. Toe-walking, repetitive shifting of weight from one foot to the other, and
retropulsion (first step is backwards) are common.

Other features may occur, but are not seen uniformly. These include seizures, teeth grinding (bruxism),
disturbed sleep, and abnormal breathing patterns consisting of breath-holding or hyperventilation, or
both. Abnormal breathing patterns, just like stereotypic hand movements, occur only during wakefulness
and increase with excitement or stress. Scoliosis develops in most young females, with approximately 10%
requiring surgery.[27,28] Additional features may include gastroesophageal reflux and other evidence of
gastrointestinal dysmotility, including chewing and swallowing dysfunction, poor stomach emptying and
constipation, cold, often purplish extremities (e.g., in the feet), osteopenia with increased incidence of
fractures[29] and ECG changes, including prolonged QT syndrome.[30]

Rett syndrome has a very consistent temporal profile ( Box 3 ). First comes the period of regression. Then,
development stabilizes with disappearance of the autistic-like features and emergence of markedly
improved interaction and socialization. Eye contact resumes to a variable degree and the ability to make
choices can be developed. However, during this period, seizures and irregular breathing may be much
more prominent. These tend to diminish during adolescence or somewhat later, along with reduced
frequency and intensity of hand stereotypies. The absence of further cognitive loss provides strong support
for employing therapies to maximize communication and socialization capabilities and to preserve mot or
function. This is also in line with the notion that RS is not a progressive disorder and could respond to
fundamental therapies aimed at a cure. Although much work remains, we now have a better understanding
of the natural history of RS, including survival and the many medical issues associated with it.[31]

Box 3. Temporal Profile in Rett Syndrome

 Early development appears to progress normally

 Developmental progress stagnates
 Frank regression ensues with poor social contact and loss of communication and finger skills
 Stabilization during early school-age children with improved social contact, eye gaze and communication
skills; motor functions slow down gradually

 Medical Issues

A wide variety of medical issues will be considered in the following paragraphs. Not all girls or women will
manifest every one, but the care provider should be aware of them should problems arise that are
otherwise unexplainable.[31,32]

 Growth

Pervasive failure of growth is typical. As stated previously, the first evidence is often a deceleration in the
rate of head growth beginning at 3 months of age.[26] Deceleration in the rate of weight gain also appears
in the 1st year of life, and deceleration in the rate of linear growth becomes noticeable after the first
birthday. The median value for head circumference approaches the second percentile value for the normal
female population by 2 years of age.

Hand and foot growth also diminish, more so for feet than hands.[33] Nonetheless, both tend to be smaller
than in the general population. The decline in the rate of foot growth follows the pattern of decline in linear
growth rate.

 Epilepsy

Reported rates for occurrence of epilepsy are quite variable, ranging from a low of 20-25% to a high of
more than 80%. Our experience, based on video-EEG monitoring, suggests that as few as 25% of clinical
behaviors are epileptic seizures that require medical management.[34] Many of the events that parents,
teachers and other caregivers report as seizures are not associated with abnormal cortical discharges when
captured by video EEG. However, subtle clinical events identified by video EEG as representing seizures
may not be appreciated by parents as such. Seizures may be generalized, focal, or atypical absence in
character and, in some small numbers, may represent infantile spasms. Should any question arise
regarding the possible occurrence of seizures, video-EEG monitoring is recommended or, at the very least,
prolonged ambulatory monitoring with automatic spike-detection capabilities.

The management of seizures in general involves available medications designed specifically to control
epilepsy. A number of these medications may be effective (e.g., carbamazepine or oxcarbazepine, valproic
acid or sodium valproate and newer medications including lamotrigine, zonisamide and levetiracetam).
The importance of being certain that the diagnosis of seizures is correct should be emphasized in order to
minimize the number of girls that are placed on these medications.

 Sleep

Sleep is often disrupted with frequent night-time awakenings, in many instances without evidence of
distress but, rather simply, playing in bed, occasionally punctuated by laughter for no apparent reason. On
other occasions, sleep is interrupted by evidence of upset or fussiness in which case it is important to be
certain that general care issues are addressed, such as the need for diaper change or hunger, or other
medical issues, such as constipation, gastroesophageal reflux or even an intercurrent infection (e.g., an
upper respiratory infection, otitis media or urinary tract infection). The importance of ruling out hunger
and other gastrointestinal issues cannot be stressed too strongly. Evidence of excessive daytime sleepiness,
that is, frequent napping, should alert the clinician to monitor night-time sleep for disruptions that might
be caused by airway obstruction during sleep. When studied in detail, it is quite clear that stage rapid eye
movement sleep is substantially reduced in RS. In addition, other sleep stages are also abnormal.[35]

Good sleep hygiene is essential. Going to bed and awakening from sleep should occur at consistent times. In
the morning, the use of a bright light will encourage arousal; in the evening, a dim light will promote going
to sleep. If going to and staying asleep are problematic, such that the family life is disrupted or the quality
of life is adversely impacted, medications should be considered. Clearly, if the parents are not obtaining
adequate rest, their ability to care for their daughter will be adversely affected. Several medications may be

effective for achieving sleep. These have included an antihistamine, such as hydroxyzine, as well as other
classes, such as the benzodiazepines or melatonin. The antihistamines may have initial effectiveness, but for
only a short time owing to the development of tolerance. Melatonin may be helpful in inducing sleep,
although it may not decrease or prevent arousals during the night. Trazodone and the newer
nonbenzodiazepine agents, such as zolpidem, may be helpful and safe in promoting a full night of sleep.
Chloral hydrate is also an effective medication that can be used safely in quantities up to 50 mg/kg/dose.
However, it is most commonly formulated as a liquid that will often be refused because of its taste unless
administered by gastrostomy. It may be found as a gel cap and some private pharmacies are able to
formulate it in a capsule or as a suppository, very acceptable options.

 Breathing Irregularities

Periodic breathing in the form of breath holding and hyperventilation, or both, is quite common.[35] These
activities occur only during wakefulness and are modified by factors such as hunger, agitation and other
stressful situations. Irregular breathing usually begins well after the other features of RS are clearly
apparent but is typically present by early childhood with a peak of occurrence in the school -age period
through to adolescence. Breath holding in particular may be quite prolonged and associated with color
changes around the mouth or in the nailbed. These events are not known to cause additional medical
problems. Breath holding can be quite subtle and often first apparent by the sudden expulsion of air (air
puffing). Breath holding may also be accompanied by copious air swallowing, producing significant
abdominal distension. This distension will dissipate on its own during periods of quiet breathing or sleep,
but for some girls can be extremely distressful.

Various approaches have been attempted to mitigate the irregular breathing with variable success.
Naltrexone or magnesium citrate has been found to be effective in some individuals. Naltrexone has been
utilized in doses ranging from 1 to 3 mg/kg/day. In our own study, we were limited to 1 mg/kg/day. In this
study, it appeared that naltrexone was exerting its effect simply by producing sedation.[36] The utilization
of any particular agent has not been promoted in the absence of systematic studies showing efficacy.

 Gastrointestinal Issues

Gastrointestinal issues in RS may represent the single most vexing medical issue, covering the gamut from
top to bottom.[37] Chewing and swallowing are often performed poorly with evidence on imaging studies of
poor coordination in the movement of food from oropharynx to the hypopharynx and dysmotility in
transiting the esophagus. Choking is a common complaint, particularly on thin liquids, often requiring the
use of thickening agents to obviate possible aspiration. If laryngeal penetration is observed on swallowing
or upper gastrointestinal imaging studies, caution should be given to continuing oral feeding (see later).
Conversely, dry foods may require moistening with liquids, such as sauces or gravies.

Gastroesophageal reflux is also common and can be confirmed by swallowing and upper gastrointestinal or
pH probe studies. In some instances, gastroesophageal reflux rises to the larynx. As such, it is important to
investigate both primary and secondary aspirations. Antireflux medications should be utilized as needed, to
inhibit acid production and promote gastric emptying. In the absence of treatment, one runs the risk of
developing a chronic or persistent esophagitis, Barrett's esophagus and secondary esophageal changes,
including cancer, ulceration or stricture. Gastroesophageal reflux may be enhanced by delayed gastric
emptying, for which the clinician should be alert and may wish to evaluate with radionuclide study.

Constipation is also a significant problem, further reflecting the poor motility of the intestinal tract. In
some instances, stool retention will produce marked enlargement of the colon. In order to prevent the
adverse consequences of constipation, a variety of strategies can be employed including GlycoLax increased
fiber in the diet and adequate fluid intake. This should ensure that a bowel movement occurs every day or
two. Some parents have complained that the generic form produces excessive gas.

Finally, gallbladder disease, gallstones or reduced function, appears to be another consideration in RS,

related to reduced motility and delayed emptying of the gallbladder. Gallbladder disease has been
recognized in the pediatric age range, as well as in adulthood. Of those with gallbladder disease known to
IRSA, nearly 40% are under the age of 20 years. In some instances, abdominal ultrasound fails to identify
gallbladder disease, suggesting that a hepatobiliary iminodiacetic acid (HIDA) scan should be considered
when other explanations for abdominal discomfort are lacking.

In summary, any period of inconsolable crying, apparent distress, night-time awakenings or undue
irritability should provoke a thorough evaluation of gastrointestinal function to c-onsider the problems
noted previously.

 Nutrition

Assuring adequate nutrition in RS is critical. It does appear that girls with RS have a well-above average
daily protein and calorie intake requirement.[38] As such, particular attention must be given to meeting
nutritional requirements and, if necessary, to providing high-calorie nutritional supplements or frequent
snacks, including lower cost supplements, such as Carnation Instant Breakfast™, and milkshakes
with additional nutritional ingredients. Appropriate vitamin supplementation should be provided.
However, one should be aware that nutritional supplements are so enriched in vitamins that excessive
vitamin intake must be avoided. As girls with RS tend to be small in stature, it is appropriate to monitor
BMI as an indicator of nutritional well-being (BMI is calculated by multiplying the weight in kg by 10,000
and dividing by the square of the patient's height in cm).

When adequate calories cannot be taken by mouth or primary aspiration prevents oral feeding,
gastrostomy or gastrojejunostomy feedings are required. Depending on the presence of gastroesophageal
reflux, a fundoplication may be required at the same time. Any girl who has failed to gain weight for 6
months to 1 year, or is losing weight, should be considered for this alternative feeding method.

 Osteopenia

Osteopenia occurs quite commonly in RS, being more significant in those girls or women who have
inadequate calorie and protein intake.[29] Even in those who have adequate protein calorie intake,
osteopenia is present, but to a lesser degree. Owing to the frequency and extent of osteopenia, fractures are
much more common.[29] As such, the possibility of a fracture should be considered if use of an extremity
ceases suddenly despite the absence of complaints. Fractures often go undetected because of the girls'
inability to express and localize pain. Regardless of age, consideration should be given to oral calcium
supplementation, beginning in childhood based on recommended daily amounts (preadolescents: 800 mg;
adolescents: 1300 mg; adults: 1000 mg and postmenopausal women: 1500 mg). Systematic studies on the
occurrence of, and possible therapies for, osteopenia are ongoing at the Baylor College of Medicine (TX,
USA) under the direction of Kathleen Motil.

 Scoliosis

Scoliosis occurs with increasing frequency in RS, beginning as early as age 5 years and occurring in at least
80% of patients by the age of maturity.[28] Scoliosis tends to be more significant in those girls who are not
ambulatory. Scoliosis often progresses dramatically and at curvatures above 40° corrective surgery
should be considered. At lesser degrees of curvature, body jackets have been employed. No systematic
studies have been performed to judge their efficacy. However, they remain an option in retarding the
progression of scoliosis. Regardless of ambulation status, proper upright positioning is critical, including
lateral supports for those in wheelchairs. Once girls with RS have matured and are through puberty,
further progression of scoliosis is generally considered to be unlikely.

 Ambulation

Up to 80% of girls with RS acquire the ability to walk. During the course of their developmental

regression, approximately a quarter of this group will lose this ability. Overall, approximately 60% remain
ambulatory.[25] Toe walking is common, as well as abnormal foot postures in which case ankle/foot
orthoses or other orthotic devices should be implemented. Significant effort should be allocated to
maintaining ambulation as long as possible. In those girls who do not walk, standing frames should be
employed both at home and at school along with parallel bars to promote supported ambulation.

 Sexual Maturation & Gynecologic Issues

As adolescence approaches, puberty should be anticipated. Ordinarily, girls with RS will enter puberty at
similar ages to their peers. As these young women are quite vulnerable, appropriate consideration should
be given to protecting them from unwarranted contact.

Menstrual cycles generally occur with predictable regularity after they have become established. Parents
or other responsible caregivers may choose to deal with these in the usual fashion or may choose one of a
variety of strategies to eliminate or minimize menstrual flow. These include Depo-Provera, birth-control
pills, or endometrial oblation. Depo-Provera is not recommended, primarily because it adversely affects
bone mineralization, but also because of its long period of action should other side effects arise. The use of
birth-control pills is common and completely acceptable. Formulations of levonorgestrel/ethinyl estradiol
provide menstrual management for 1 year (marketed as Lybrel®) or for 90 days (marketed as Seasonale®
or Seasonique®), such that menstrual flow can be effectively eliminated or minimized.

When unexplained irritability or inconsolable crying occurs, consideration should be given to a possible
gynecologic issue. An abdominal ultrasound, as well as consultation with a gynecologist, should be
considered strongly.

 Cardiac & Autonomic Systems

A prolonged QT interval and ST-segment changes may be observed with increasing frequency through the
age range.[30,32] As such, at the time of diagnosis, an ECG is recommended to assess QTc or other
significant abnormality. If normal, repeating the cardiogram in 2-3 years is appropriate. If abnormal,
referral to a cardiologist for consideration of an appropriate intervention strategy is indicated. Prolonged
QTc is a quite treatable problem with medication and should not be overlooked. Should a QT-segment
abnormality be identified, it would be appropriate to have other members of the patient's family screened
in the event this finding is unrelated to the RS.

The hands and feet tend to be cool to cold in RS. This is more typically noted in the lower extremities and
may consist not only of cold but discolored feet, ranging from red and mottled to purple, and extending
well up on the lower extremity. This finding is believed to be related to excess sympathetic nervous system
tone. No specific intervention is available, but it is important to keep the hands and feet appropriately
warm.

 Bruxism

Bruxism (teeth grinding) occurs in virtually all girls at some point in time, varying in frequency and
intensity, and exacerbated by anxiety, excitement or stressful situations. The sound created is really quite
characteristic, having been described by Bengt Hagberg as that of slowly uncorking a bottle of wine.

Efforts to reduce the teeth grinding are generally unrewarding. Over time, they diminish, in many actually
disappearing after school age.

 Other Motor System Functions

Hypotonia is the rule early in RS. Over time, muscle tone may be increased, representing rigidity rather

than spasticity (upper motor neuron signs are generally absent). During this period, motor activities,
including hand stereotypies and ambulation persist when present, but their speed slows down.

Other disorders of movement occur, including tremor, myoclonus and choreiform activities.[39] Tremor is
particularly apparent upon awakening from sleep or a nap, or when placed in an unstable position, such as
upright on their feet or on the edge of a chair or lap. Myoclonus may be focal or multifocal and can also be
exacerbated by excitement or anxiety. Focal or multifocal dystonia, especially at the ankles and feet, and at
the wrists and hands, is common, particularly with advancing age. Without proper alignment, contractures
can develop at the involved joints, particularly when sitting in a wheelchair for long periods of time without
effective mobilization. In those girls who tend to keep their hands together in the midline at the chest level,
contractures at the elbows and, to some extent, limitation of motion at the shoulders will develop. Ankle-
foot orthoses or elbow splinting may reduce the risk for development of contractures. Botulinum toxin may
be effective in all-eviating limitations of joint movement.

 Longevity

Unlike the original suggestion that RS is a progressive neurodegenerative disorder, it is now understood to
be a neurodevelopmental disorder, with prolonged survival likely. Current intervention strategies are
much more aggressive than 20-30 years ago. This alone would be expected to lead to greater longevity. We
are aware of many women that have survived into their 40s and 50s, and expect that with proper nutrition
and medical care, prolonged survival is indeed likely to be the rule. Few systematic studies of survival have
been conducted. A prior unpublished study conducted while the author was at Baylor noted that survival
through age 10 years was normal, whereas survival through to age 35 years was approximately 70% of the
normal female population. More recently, preliminary information from a cohort of more than 1900 US
and Canadian females indicates at least 80% survival to the age of 20 years and 50% survival for those
over 50 years of age. These data are similar to those recently reported from Australia.[6] The consequence
of prolonged survival is that, in many cases, parents or other caregivers will themselves be elderly and due
consideration must be given to long-term care of these women when their parents are no longer able to
provide it.

Sudden death has also been described in RS. In most cases the actual cause is unclear, but may well involve
autonomic dysfunction or a cardiac conduction system abnormality, such as prolonged QT.

 Clinical Research

Current clinical research is focused on refining the clinical aspects of RS, including its natural history and
quality of life, both for the participants and their principal care providers, and on developing effective
intervention strategies. The current US Clinical Research Consortium has three sites: Baylor College of
Medicine, Greenwood Genetic Center in Greenwood (SC), the University of Alabama at Birmingham (AL)
and a data coordinating site at the University of South Florida (FL) that ma-intains a public website.[101]

 Molecular Neurobiology

Dramatic advances in our understanding of the neurobiologic aspects have occurred over the past few
years. These have emanated in large part from molecular neurobiologic studies of MECP2 in mouse models
for RS. Studies in a knockin mouse model demonstrated abnormal social behaviors and poor spatial and
contextual fear memory.[3] Similar findings were reported from a knockout mouse model.[40] Knockout
mice were shown to have reduced levels of brain-derived neurotrophic factor (BDNF), and mice lacking
BDNF had features similar to Mecp2 knockout mice.[41,42] When BDNF was overexpressed in these mice,
onset of Rett-like behaviors was delayed, but brain weight did not increase.

Regulation of breathing is a key abnormality in RS. Reduced levels of norepinephrine and serotonin were
observed in the brainstem (medulla) respiratory control pathways in knockout mice and supplementation
of norepinephrine stabilized the respiratory control network.[43] Subsequent studies demonstrated that

desipramine, an inhibitor of norepinephrine reuptake, improved breathing abnormalities substantially,
prolonged survival by several weeks and increased the number of tyrosine hydroxylase-containing neurons
in the brainstem.[44]

Studies on the longitudinal expression pattern of MECP2 in cortical neurons from female knockout mice
suggest a change in X-chromosome inactivation status with increasing age, that is, cells that express the
wild-type protein increased from 50 to 70%. One might speculate that this change can be related to the
pattern of stabilization and improved interaction in older girls.[45]

Very recent results suggest a neuroendocrine component to RS. Studies in a knockin mouse model revealed
increased corticosterone release and Crh expression, not only in the hypothalamus, but also in the
amygdala and stria terminalis.[4] Furthermore, the authors showed that MECP2 binds to the Crh
promoter and may regulate its expression. Mutant MECP2 does not bind to this promoter. The amygdala
has important downstream connections to autonomic system nuclei subserving gastrointestinal, respiratory
and cardiovascular functions. As anxiety and fear are common clinical features in RS, these results provide
a potential therapeutic avenue.

Studies in human tissues revealed abnormal developmental progression of serotonin-transporter binding in
the brainstem from individuals with RS with increasing age, compared with controls, providing further
evidence of dysregulation of gastrointestinal and cardiac responses.[46] Along the same lines, MECP2 also
regulates IGFBP3[47] and AVP in brain tissue.[48]

 Therapeutic Intervention

Individuals with RS require a variety of therapies throughout their lives.[49] These include physical and
occupational therapies to promote sitting, standing, ambulation and fine motor functions. Wherever
necessary, standing frames and devices that assist with walking should be employed. In some cases,
adaptive equipment, such as tricycles, may be considered and some girls may use small trampolines or
treadmills. Hippotherapy and swimming are extremely popular and well tolerated by most individuals with
RS. In terms of fine motor skills, goals in therapy must be realistic and, when improvements or
advancements do occur, it often requires daily repetition to preserve them.

As they mature, individuals with RS give intense eye contact, which may be employed to develop
communication skills, such as choice making, using simple picture boards or sophisticated computer -based
technologies. Some girls are able to use their hands to activate switches; others can use ocular devices to ac-
tivate switches. These opportunities to make choices in all aspects of their lives, ranging from eating, to
socializing, to types of entertainment, should be maximized. Music seems to be particularly appealing, with
each girl or woman developing her own preference panel probably based on what music is played within
the home.

 Emerging Therapeutic Strategies

The complexities of gene therapy coupled with the specific requirement to correct only cells with
abnormalities in MECP2 render gene-based therapies for RS problematic at this time. One promising
strategy is to identify pharmacologic agents capable of correcting so-called 'stop' (nonsense) mutations by
reading through the premature stop codon to produce a full-length protein. Efforts are currently underway
to develop such agents. This strategy is particularly attractive in that approximately a third of MECP2
mutations in RS are the nonsense type. Alternatively, therapies directed at known MECP2 gene targets, as
noted previously for the gene encoding Crh, suggest another avenue for therapy. Agents that would directly
downregulate Crh might offer the possibility to intervene fundamentally in Crh-related systems and, in
particular, to modify anxiety and fear that are quite prominent in individuals with RS. Efforts to identify
or develop these agents should be considered. Alternatively, an indirect approach would be to employ
available pharmacologic agents, such as the serotonin-reuptake inhibitor class of drugs, to address the core
problems of anxiety and fear or the norepinephrine reuptake inhibitors to address p-eriodic breathing

patterns.

The previously noted abnormal development of serotonin-transporter binding in postmortem samples of
brainstem nuclei from girls or women with RS[46] and the mouse model studies showing beneficial effects
of desipramine, provide additional support for establishing clinical trials of serotonin and/or
norepinephrine reuptake inhibitors in order to address the significant dysregulation of gastrointestinal and
respiratory function.

 Expert Commentary & Five-year View

The pace of advancement in understanding the clinical and basic science aspects of RS since the
identification of mutations in the MECP2 gene in 1999 has been extraordinary. To date, studies have
expanded the severity range of clinical involvement associated with such mutations to encompass not only
RS, but also learning disabilities and autism on the one hand, and severe encephalopathy on the other, and
have advanced clinical interventions dramatically such that the long-term outlook is very different today.
Together with recent studies aimed at identifying the fundamental role of MECP2 in developmental
neurobiology and the proof-of-principle studies in the mouse model regarding reversibility, clinical and
basic science investigators seem poised for even more dramatic advances in the coming 5 years. During this
period, the molecular targets of MECP2 will be more fully explained, enhancing possibilities for developing
specific therapies.

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Websites

Rare Diseases Clinical Research Network http://rarediseasesnetwork.epi.usf.edu/

Addendum

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The author: Professor Yasser Metwally, professor of neurology, Ain Shams university, Cairo, Egypt

www.yassermetwally.com

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