Rett's Syndrome, Rhett Syndrome, Rett Syndrom
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. When functioning normally,
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 of the
protein are formed. The absence of the protein causes other genes to be
switched on and stay on at inappropriate stages, forming excessive amounts
of proteins. This, in turn, may cause the neurodevelopmental problems that
are characteristic of the disorder.
Seventy to 80 percent of girls given a diagnosis of Rett syndrome have
the MECP2 genetic mutation. Scientists believe the remaining 20 to 30
percent of cases may be caused 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 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 to determine if they are asymptomatic carriers of the disorder,
which is a 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 the MECP2 mutation. 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 the defect die shortly before
or after birth.
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 identify 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" 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 congenital (at or before birth) onset, 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 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 number of cells, the symptoms will be mild, but
if a larger percentage of cells have the healthy X chromosome 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 precisely regulated pattern of development 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.
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International Rett Syndrome Association
9121 Piscataway Road,
Suite 2B
Clinton, MD 20735
(301) 856-3334
(800)
818-7388
www.rettsyndrome.org
Rett Syndrome Research Foundation
4600 Devitt
Drive
Cincinnati, OH 45246
(513) 874-3020
www.rsrf.org
Easter Seals
230 W. Monroe Street, Suite 1800
Chicago, IL
60606-4802
(312) 762-6200
(800) 221-6827
www.easter-seals.org
National Institute of Child Health and Human
Development
Building 31, Room 2A32
Bethesda, MD
20892-2425
(301) 496-5133
www.nichd.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.
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