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Rett Syndrome Fact Sheet
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A publication of National Institute of Neurological
Disorders and Stroke
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Reviewed October 9, 2003
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Approx. 8 pages when printed.
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Rett syndrome is a childhood neurodevelopmental
disorder characterized by normal early development
followed by loss of purposeful use of the hands,
distinctive hand movements, slowed brain and head
growth, gait abnormalities, seizures, and mental
retardation. It affects females almost exclusively.
The disorder was identified by Dr. Andreas Rett, an
Austrian physician who first described it in a
journal article in 1966. It was not until after a
second article about the disorder was published in
1983 that the disorder was generally recognized.
The course of Rett syndrome, including the age of
onset and the severity of symptoms, varies from child
to child. Before the symptoms begin, however, the
child appears to grow and develop normally. Then,
gradually, mental and physical symptoms appear.
Hypotonia (loss of muscle tone) is usually the first
symptom. As the syndrome progresses, the child loses
purposeful use of her hands and the ability to speak.
Other early symptoms may include problems crawling or
walking and diminished eye contact. The loss of
functional use of the hands is followed by compulsive
hand movements such as wringing and washing. The
onset of this period of regression is sometimes
sudden.
Another symptom, apraxia — the inability to
perform motor functions — is perhaps the most
severely disabling feature of Rett syndrome,
interfering with every body movement, including eye
gaze and speech.
Individuals with Rett syndrome often exhibit
autistic-like behaviors in the early stages. Other
symptoms may include toe walking; sleep problems;
wide-based gait; teeth grinding and difficulty
chewing; slowed growth; seizures; cognitive
disabilities; and breathing difficulties while awake
such as hyperventilation, apnea (breath holding), and
air swallowing.
There are four stages of Rett syndrome. Stage I,
called early onset, generally begins between 6 and 18
months of age. Quite frequently, this stage is
overlooked because symptoms of the disorder may be
somewhat vague, and parents and doctors may not
notice the subtle slowing of development at first.
The infant may begin to show less eye contact and
have reduced interest in toys. There may be delays in
gross motor skills such as sitting or crawling.
Hand-wringing and decreasing head growth may occur,
but not enough to draw attention. This stage usually
lasts for a few months but can persist for more than
a year.
Stage II, or the rapid destructive stage, usually
begins between ages 1 and 4 and may last for weeks or
months. This stage may have either a rapid or a
gradual onset as purposeful hand skills and spoken
language are lost. The characteristic hand movements
begin to emerge during this stage and often include
wringing, washing, clapping, or tapping, as well as
repeatedly moving the hands to the mouth. Hands are
sometimes clasped behind the back or held at the
sides, with random touching, grasping, and releasing.
The movements persist while the child is awake but
disappear during sleep. Breathing irregularities such
as episodes of apnea and hyperventilation may occur,
although breathing is usually normal during sleep.
Some girls also display autistic-like symptoms such
as loss of social interaction and communication.
General irritability and sleep irregularities may be
seen. Gait patterns are unsteady and initiating motor
movements can be difficult. Slowing of head growth is
usually noticed during this stage.
Stage III, also called the plateau or
pseudo-stationary stage, usually begins between ages
2 and 10 and can last for years. Apraxia, motor
problems, and seizures are prominent during this
stage. However, there may be improvement in behavior,
with less irritability, crying, and autistic-like
features. An individual in stage III may show more
interest in her surroundings, and her alertness,
attention span, and communication skills may improve.
Many girls remain in this stage for most of their
lives.
The last stage, stage IV — called the late
motor deterioration stage — can last for years
or decades and is characterized by reduced mobility.
Muscle weakness, rigidity (stiffness), spasticity,
dystonia (increased muscle tone with abnormal
posturing of extremity or trunk), and scoliosis
(curvature of the spine) are other prominent
features. Girls who were previously able to walk may
stop walking. Generally, there is no decline in
cognition, communication, or hand skills in stage IV.
Repetitive hand movements may decrease, and eye gaze
usually improves.
Rett syndrome is caused by mutations (structural
alterations or defects) in the MECP2 (pronounced
meck-pea-two) gene, which is found on the X
chromosome (see section on "Who gets Rett
syndrome" for a discussion of the importance of
the involvement of the X chromosome). Scientists
identified the gene — which is believed to
control the functions of several other genes —
in 1999. The MECP2 gene contains instructions for the
synthesis of a protein called methyl cytosine binding
protein 2 (MeCP2), which acts as one of the many
biochemical switches that tell other genes when to
turn off and stop producing their own unique
proteins. Because the MECP2 gene does not function
properly in those with Rett syndrome, insufficient
amounts or structurally abnormal forms of the protein
are formed. The absence or malfunction of the protein
is thought to cause other genes to be abnormally
expressed, but this hypothesis has not yet been
confirmed.
Seventy to 80 percent of girls given a diagnosis of
Rett syndrome have the MECP2 genetic mutation
detected by current diagnostic techniques. Scientists
believe the remaining 20 to 30 percent of cases may
be caused by partial gene deletions, by mutations in
other parts of the gene, or by genes that have not
yet been identified; thus, they continue to search
for other mutations.
Although Rett syndrome is a genetic disorder —
resulting from a faulty gene or genes — less
than 1 percent of recorded cases are inherited or
passed from one generation to the next. Most cases
are sporadic, which means the mutation occurs
randomly, mostly during spermatogenesis, and is not
inherited.
Rett syndrome affects one in every 10,000 to 15,000
live female births. It occurs in all racial and
ethnic groups worldwide. Prenatal testing is
available for families with an affected daughter who
has an identified MECP2 mutation. Since the disorder
occurs spontaneously in most affected individuals,
however, the risk of a family having a second child
with the disorder is less than 1 percent.
Genetic testing is also available for sisters of
girls with Rett syndrome and an identified MECP2
mutation to determine if they are asymptomatic
carriers of the disorder, which is an extremely rare
possibility.
Girls have two X chromosomes, but only one is active
in any given cell. This means that in a child with
Rett syndrome only about half the cells in the
nervous system will use the defective gene. Some of
the child's brain cells use the healthy gene and
express normal amounts of the proteins.
The story is different for boys who have an MECP2
mutation known to cause Rett syndrome in girls.
Because boys have only one X chromosome they lack a
back-up copy that could compensate for the defective
one, and they have no protection from the harmful
effects of the disorder. Boys with such a defect die
shortly after birth.
Different types of mutations in the MECP2 gene can
cause mental retardation in boys.
Doctors diagnose Rett syndrome by observing signs and
symptoms during the child's early growth and
development, and conducting ongoing evaluations of
the child's physical and neurological status.
Recently, scientists developed a genetic test to
confirm the clinical diagnosis of this disorder; the
test involves searching for the MECP2 mutation on the
child's X chromosome. Given what we know about
the genes involved in Rett syndrome, such tests are
able to confirm a clinical diagnosis in up to 80
percent of all cases.
Some children who have Rett syndrome-like
characteristics or MECP2 genetic mutations do not
fulfill the diagnostic criteria for the syndrome as
defined below. These persons are described as having
"atypical" or "variant" Rett
syndrome. Atypical cases account for about 15 percent
of the total number of diagnosed cases.
A pediatric neurologist or developmental pediatrician
should be consulted to confirm the clinical diagnosis
of Rett syndrome. The physician will use a highly
specific set of guidelines that are divided into
three types of clinical criteria: essential,
supportive, and exclusion. The presence of any of the
exclusion criteria negates a diagnosis of
"classic" or "typical" Rett
syndrome.
Examples of essential diagnostic criteria or symptoms
include having apparently normal development until
between the ages of 6 and 18 months and having normal
head circumference at birth followed by a slowing of
the rate of head growth with age (between 3 months
and 4 years). Other essential diagnostic criteria
include severely impaired expressive language,
repetitive hand movements, shaking of the torso, and
toe-walking or an unsteady, wide-based, stiff-legged
gait.
Supportive criteria are not required for a diagnosis
of Rett syndrome but may occur in some patients. In
addition, these symptoms — which vary in
severity from child to child — may not be
observed in very young girls but may develop with
age. A child with supportive criteria but none of the
essential criteria does not have Rett syndrome.
Supportive criteria include breathing difficulties;
electroencephalogram (EEG) abnormalities; seizures;
muscle rigidity, spasticity, and/or joint contracture
which worsen with age; scoliosis; teeth-grinding;
small feet in relation to height; growth retardation;
decreased body fat and muscle mass (although there
may be a tendency toward obesity in some affected
adults); abnormal sleep patterns, irritability, or
agitation; chewing and/or swallowing difficulties;
poor circulation of the lower extremities with cold
and bluish-red feet and legs; decreased mobility with
age; and constipation.
In addition to the essential diagnostic criteria, a
number of specific conditions enable physicians to
rule out a diagnosis of Rett syndrome. These are
referred to as exclusion criteria. Children with any
one of the following criteria do not have Rett
syndrome: enlargement of body organs or other signs
of storage disease, vision loss due to retinal
disorder or optic atrophy, microcephaly at birth, an
identifiable metabolic disorder or other inherited
degenerative disorder, an acquired neurological
disorder resulting from severe infection or head
trauma, evidence of growth retardation in utero, or
evidence of brain damage acquired after birth.
The course and severity of Rett syndrome vary from
individual to individual. Some girls have symptoms
from birth onward, while others may have late
regression or milder symptoms.
Because females have two copies of the X chromosome
and need only one working copy for genetic
information, they turn off the extra X chromosome in
a process called X inactivation. This process occurs
randomly so that each cell is left with one active X
chromosome. The severity of Rett syndrome in girls is
in part a function of the percentage of cells with a
normal copy of the MECP2 gene after X inactivation
takes place: if X inactivation turns off the X
chromosome that is carrying the defective gene in a
large proportion of cells, the symptoms will be mild,
but if a larger percentage of cells have the X
chromosome with the normal MECP2 gene turned off,
onset of the disorder may occur earlier and the
symptoms may be more severe.
There is no cure for Rett syndrome. Treatment for the
disorder is symptomatic — focusing on the
management of symptoms — and supportive,
requiring a multidisciplinary approach. Medication
may be needed for breathing irregularities and motor
difficulties, and antiepileptic drugs may be used to
control seizures. There should be regular monitoring
for scoliosis and possible heart abnormalities.
Occupational therapy (in which therapists help
children develop skills needed for performing
self-directed activities — occupations —
such as dressing, feeding, and practicing arts and
crafts), physiotherapy, and hydrotherapy may prolong
mobility. Some children may require special equipment
and aids such as braces to arrest scoliosis, splints
to modify hand movements, and nutritional programs to
help them maintain adequate weight. Special academic,
social, vocational, and support services may also be
required in some cases.
Despite the difficulties with symptoms, most
individuals with Rett syndrome continue to live well
into middle age and beyond. Because the disorder is
rare, very little is known about long-term prognosis
and life expectancy. While it is estimated that there
are many middle-aged women (in their 40s and 50s)
with the disorder, not enough women have been studied
to make reliable estimates about life expectancy
beyond age 40.
Within the Federal Government, the National Institute
of Neurological Disorders and Stroke (NINDS) and the
National Institute of Child Health and Human
Development (NICHD), two of the National Institutes
of Health (NIH), support clinical and basic research
on Rett syndrome. Understanding the cause of this
disorder is necessary for developing new therapies to
manage specific symptoms, as well as for providing
better methods of diagnosis. The discovery of the
Rett syndrome gene in 1999 provides a basis for
further genetic studies and enables the use of
recently developed animal models such as transgenic
mice.
One NINDS-supported study is looking for mutations in
the MECP2 gene of individuals with Rett syndrome to
find out how the MeCP2 protein functions. Information
from this study will increase understanding of the
disorder and may lead to new therapies.
Scientists know that lack of a properly functioning
MeCP2 protein disturbs the function of mature brain
cells but they do not know the exact mechanisms by
which this happens. Investigators are also trying to
find other genetic mutations that can cause Rett
syndrome and other genetic switches that operate in a
similar way to the MeCP2 protein. Once they discover
how the protein works and locate similar switches,
they may be able to devise therapies that can
substitute for the malfunctioning switch. Another
outcome might involve manipulating other biochemical
pathways to compensate for the malfunctioning MECP2
gene, thus preventing progression of the disorder.
Private, voluntary organizations that offer
information and services to those affected by Rett
syndrome include the following:
Information temporarily unavailable. Please check
back Tuesday, May 4, 2005. Thank you for your
patience.
Information temporarily unavailable. Please check
back Tuesday, May 4, 2005. Thank you for your
patience.
Information temporarily unavailable. Please check
back Tuesday, May 4, 2005. Thank you for your
patience.
In addition to the NINDS, the following institute
within the National Institutes of Health supports
research on Rett syndrome:
Information temporarily unavailable. Please check
back Tuesday, May 4, 2005. Thank you for your
patience.
For information on other neurological disorders or
research programs funded by the National Institute of
Neurological Disorders and Stroke, contact the
Institute's Brain Resources and Information
Network (BRAIN) at:
BRAIN
P.O. Box 5801
Bethesda, MD 20824
(800) 352-9424
www.ninds.nih.gov
1Rett A. On an unusual brain atropic syndrome with
hyperammonemia in childhood. Wien Med Wochenschr
1966; 116:723-726.
2Hagberg B, Aicardi J, Dias K, Ramos O. A progressive
syndrome of autism dementia, ataxia, and loss of
purposeful hand use in girls: Rett's syndrome:
report of 35 cases. Ann Neurol 1983; 14:471-479.
NIH Publication No. 04-4863
December 2003
Prepared by:
Office of Communications and Public Liaison
National Institute of Neurological Disorders and
Stroke
National Institutes of Health
Bethesda, MD 20892
NINDS health-related material is provided for
information purposes only and does not necessarily
represent endorsement by or an official position of
the National Institute of Neurological Disorders and
Stroke or any other Federal agency. Advice on the
treatment or care of an individual patient should be
obtained through consultation with a physician who
has examined that patient or is familiar with that
patient's medical history.
All NINDS-prepared information is in the public
domain and may be freely copied. Credit to the NINDS
or the NIH is appreciated.
Reviewed October 9, 2003
Copyright © 2007 ASGC. All rights reserved.
Autism Society of Greater Cleveland
P.O. Box 41066, Brecksville, Ohio 44141 (216) 556-4937
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