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Fragile
X
Introduction
Fragile X syndrome is the most common genetically inherited form of mental
retardation currently known. In addition to intellectual disability, some
individuals with Fragile X display common physical traits and characteristic
facial features, such as prominent ears. Children with Fragile X often appear
normal in infancy but develop typical physical characteristics during their
lifetime. Mental impairment may range from mild learning disability and
hyperactivity to severe mental retardation and autism. This genetic syndrome is
caused by a defect on the X chromosome. Because of scientific advances,
improvements in genetic testing, and increased awareness, the number of children
diagnosed with Fragile X has increased significantly over the last decade.
A substantial research effort
led to the 1991 discovery of FMR-1 (Fragile X mental retardation), the gene that
when damaged causes Fragile X. Although the normal function of the FMR-1 gene is
not fully understood, it appears to be important early in development. The
mechanism by which the normal FMR-1 gene is converted into an altered, or
mutant, gene capable of causing disease symptoms involves an increase in the
length of the gene. A small region of the gene, CGG, undergoes repeated
duplications, forming deoxyribonucleic acid (DNA) repeats that result in a
longer gene. The lengthened DNA region is susceptible to a chemical modification
process called DNA methylation. When the number of repeats is small (less than
200) the individual often has no signs of the disorder. However, in individuals
with a larger number of repeats, the characteristics that are typical of Fragile
X are observed. In families that exhibit Fragile X, both the number of repeats
and the length of the chromosome increase with succeeding generations. The
severity of the symptoms increases with the increasing length of the repeated
region.
Fragile
X exhibits X-linkage. The effect of X-linkage is that the frequency of the
syndrome is greater in males than in females. To understand the mechanism of
X-linkage some background information on the organization of human chromosomes
is needed. Human females typically have two X chromosomes, and human males have
one X and one Y chromosome. A female who inherits a chromosome carrying the
Fragile X gene from either parent is likely to inherit a normal X chromosome
from the other parent. The normal X chromosome could provide the normal gene
function and mask the presence of the Fragile X gene in a female. In that case,
the female would still possess the Fragile X gene and be capable of passing it
on to her offspring, but she would not exhibit symptoms. She would be a
"carrier." On the other hand, a male who inherits the Fragile X gene
from his mother would inherit a Y chromosome and not a normal X chromosome from
his father, and therefore a male with one copy of the gene is likely to show
symptoms. We do not yet have a complete understanding of the mechanism of
genetic transmission of Fragile X. For example, it is not known why
approximately one-fifth of males who carry mutated forms of FMR-1 are either
unaffected or only mildly affected. In some cases, a single copy of the Fragile
X gene is sufficient to cause the syndrome in females. The situation is made
more complex by the fact that the intensity of the symptoms increases with
succeeding generations. The observable characteristics of Fragile X occur in
approximately 1 in 1,000 male births and 1 in 2,500 female births.
On
a normal X chromosome, the FMR-1 region of the chromosome contains 50 or fewer
copies of the CGG repeat. This same region may be repeated hundreds or even
thousands of times in individuals with Fragile X. Researchers have made a
surprising correlation between the number of DNA repeats and the degree of
clinical impairment. Individuals with between 50 and 200 repeats are often
carriers of Fragile X who have mild symptoms or no symptoms at all. When the
number of repeats increases, the chemical modification process called DNA
methylation is more likely to occur. It is this chemical modification that
appears to inactivate the FMR-1 gene, leading to deficits in cognitive
processing. Why methylation of this region of DNA leads to the symptoms of
Fragile X is not understood. Mental impairment in Fragile X appears to correlate
with DNA containing more than 200 repeats. In that case, most males are impaired
and 50 percent of females show some learning disabilities. However, there are
exceptions, including individuals with enormous numbers of repeats who have no
apparent impairment.
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Inheritance
In normal individuals the FMR-1 gene is passed on, in stable fashion, from the
parent to the offspring. In Fragile X individuals, the repeated sequences not
only expand abnormally, but are unstable and the degree of impairment in
offspring may vary. The Fragile X mutation appears to increase in length as it
is inherited by succeeding generations. This phenomenon is known as
"genetic anticipation." Eventually, the mutation reaches a critical
number of repeats and causes Fragile X syndrome. For example, a male may have
normal IQ, no Fragile X symptoms, and a short region of DNA repeats at the
Fragile X region of his X chromosome. This individual, called a
"transmitting" male, may have a daughter with 50 to 200 repeats. At
that stage the condition is considered a "premutation," as there still
may be no apparent symptoms. This daughter, a "carrier," might have a
son with 1,000 repeats and the full-blown Fragile X syndrome. If a woman is a
carrier, each of her children has a 50 percent chance of inheriting her Fragile
X gene. Each time her Fragile X gene is inherited, it is likely to have expanded
in length. A daughter who inherits the gene will be a carrier with some chance
of impairment; a son who inherits the gene has an 80 percent likelihood of
developing Fragile X syndrome.
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Testing
for Fragile X Carrier
A simple test is now available that can determine if a woman is carrier of the
Fragile X gene. A drop of blood can be taken from the woman's finger and
analyzed quickly and inexpensively. If a woman who is found to be a carrier is
pregnant, she can arrange for testing of the fetus, as described below. For a
woman with a family history of retardation, testing before pregnancy will help
determine if she is at risk.
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Prenatal
Testing
Three prenatal tests can determine if Fragile X is present in the fetus.
Chorionic villi sampling (CVS) involves extracting a tiny amount of fetal tissue
at 9 to 11 weeks of pregnancy. CVS is not widely used and carries a 1-2 percent
risk of miscarriage following the procedure.
Amniocentesis is the removal and analysis of a small sample of fetal
cells from the amniotic fluid. Amniocentesis is widely available and involves a
lower risk of miscarriage. However, amniocentesis cannot be done until the 15th
to 18th week of pregnancy and it usually takes an additional 2 to 4 weeks for
the cells to grow and be analyzed. So a woman may have to wait until the 17th to
22nd week of her pregnancy to have the results of this test.
The
third method, percutaneous umbilical blood sampling (PUBS), is the most accurate
method and can be used to confirm the results of CVS or amniocentesis. However,
PUBS is not widely available, PUBS is not done until the 18th to 22nd week and
carries the greatest risk of miscarriage.
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Diagnosing
and Treating Fragile X Syndrome
Individuals
with Fragile X may have a cluster of physical, behavioral, mental, and other
characteristics. These symptoms may vary in number and degree among affected
children. In the best of circumstances, early identification of a child with
Fragile X and subsequent treatment involves a team of professionals. These might
include a speech and language pathologist, an occupational therapist (perhaps
even a specialist in sensory integration), a physical therapist, a special
education teacher, a genetics counselor, and a psychologist.
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Physical
Characteristics
Males with Fragile X have some common physical characteristics: a long narrow
face; large or prominent ears; and macroorchidism (enlarged testicles). More
than 80 percent of males with Fragile X develop at least one of these features,
but often not until after puberty. Other physical characteristics of males with
Fragile X are double-jointed fingers, flat feet, puffy eyelids, and "hollow
chest." These physical features may indicate an underlying abnormality of
the connective tissue, although no specific connective tissue defect has been
detected. Females with Fragile X
syndrome do not exhibit most of the physical characteristics found in males with
Fragile X, although they often have large or prominent ears.
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Behavioral
Characteristics
The most prevalent behavioral characteristics of children with Fragile X are
attention problems and hyperactivity, known as attention-deficit hyperactivity
disorder (ADHD). ADHD is frequently treated with medication, generally central
nervous system stimulants such as methylphenidate (Ritalin®), pemoline (Cylert®)
and dextroamphetamine (Dexedrine®). Because these drugs have side effects that
include irritability and poor appetite, alternatives such as amantadine and
clonidine may be appropriate. Amantadine has been used with surprising success
to treat hyperactivity and attention difficulties in children with low IQs, for
whom stimulants are generally less effective.
Fragile
X children with ADHD may benefit from the addition of tricyclic antidepressants
or a major tranquilizer such as thioridazine (Mellaril®). Because mood swings
and temper tantrums present major difficulties for children with Fragile X,
psychotherapeutic medications such as Lithium and more recently fluoxetine
(Prozac®) have helped control aggression and outbursts. Anticonvulsants such as
carbamazepine or valproate, used if seizures are present, can also help treat
behavior problems, including aggression in males with Fragile X.
Children
with Fragile X have strong reactions to changes in their environment, and their
heightened anxiety can compound their behavioral difficulties. They appear to
have an underlying disability related to processing external stimuli, called
sensory integration (see Additional Therapies). Extreme hypersensitivity to
their environment makes is difficult for them to screen out stimuli such as
noise, lights, or odors. This, in turn, often provokes emotional outbursts or
tantrums.
Some
of the other behaviors associated with Fragile X are similar to those of autism,
including hand flapping, hand biting, poor eye contact, and tactile
defensiveness (responding negatively to being touched). However, one strength of
males with Fragile X is their great sociability and friendliness, in contrast to
autistic children, who appear unable to relate to others. Researchers recommend
that autistic children be screened for Fragile X.
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Mental
Impairment
Mental retardation associated with Fragile X is similar to that of Down syndrome
in that most of those affected fall somewhere in the middle range of impairment.
There are differences between males and females with Fragile X with respect to
their mental impairment. There are differences between males and females with
Fragile X with respect to their mental impairment.
Many
females with Fragile X syndrome are learning disabled in math, but perform
exceptionally well in reading and spelling. In addition, one-third of females
with Fragile X have metal disabilities similar to those associated with
schizophrenia, such as dependence on odd forms of communication and preference
for social isolation. Males with Fragile X appear to differ in mental
development from both females with Fragile X and children with other kinds of
developmental delays who exhibit learning disabilities. Males with Fragile X may
actually achieve more than some other developmentally disabled children with
higher IQ scores. It is important for educators to understand the particular
difficulties of males with Fragile X. They appear to process information in
simultaneous fashion; this causes difficulty when they are taught skills that
require sequential processing of information, such as reading. For males with
Fragile X, learning often involves seeing the whole in order to understand the
parts.
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Speech,
Language, and Learning Disabilities
Speech and language present special difficulties. Children with Fragile X often
speak in rapid bursts or repeat words (called echolalia). For males with Fragile
X, the primary language difficulty is perseveration. Perseveration is the
inability to complete a sentence because of continuous repetition of words at
the end of a phrase. Another language-based behavior displayed by males with
Fragile X is talking inappropriately and incessantly about one topic. This
particular difficulty distinguishes males with Fragile X from individuals with
other forms of mental retardation or autism. Speech problems are made worse in
situations where the child must have eye contact with another person or when the
child becomes anxious, leading researchers to suspect some underlying
relationship between difficulties with language and difficulties with sensory
processing.
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Medical
Problems
Although most children with Fragile X do not have serious physical problems,
they are at greater risk for certain types of moderate medical problems than are
normal children. For example, they often suffer recurrent otitis media (inner
ear infections), which should be treated as early as possible to prevent it from
becoming a source of language difficulties. Common eye problems include myopia
(nearsightedness) and a high incidence of "lazy eye." Orthopedic
difficulties related to flat feet and joint laxity may occur. Twenty percent of
males with Fragile X are prone to seizures, including petit mal, grand mal, and
temporal lobe seizures. In addition, many children with Fragile X have digestive
disorders, such as gastroesophageal reflux, that causes gagging, regurgitation,
and discomfort.
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Education
of Children with Fragile X
Even at a young age, children with Fragile X tend to be good at imitation and to
be very social. Consequently, they can benefit immensely from early intervention
programs and prolonged contact with children who are developing normally.
Congressional legislation (Public Law 99-457) mandates early intervention
services for children with developmental delays, ages 3 to 5 years; in some
states this includes younger children. (For help finding local programs see
Sources of Information section.)
Parents
and educators should be aware that many children with Fragile X achieve above
the level that would have been predicted from measured IQ, and it is important
for parents and educators to help these children reach their maximum potential.
Children with Fragile X with an IQ above 70 generally do best when mainstreamed
into a well-organized classroom environment with individualized help from
special education experts and other professionals. Cooperative instruction,
using peers to help teach, often relieves some of the stress of the classroom
environment and the teacher-child relationship.
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Additional
Therapies
To counter the sensory integration difficulties of children with Fragile X, a
wide range of strategies has been employed. Minimizing exposure to noise and
odors may prevent over stimulation. Therapeutic calming techniques, such as
music therapy, can also be used. It may be helpful to make special efforts to
provide structure in the immediate environment and in day-to-day activities.
Children with Fragile X often develop their own routines. Occupational
therapists specializing in sensory integration therapy can work with children
with Fragile X to help them organize environmental stimuli and to improve their
response to formal education.
The
strength of their visual memory means that children with Fragile X process
information better when they are presented with whole pictures rather than when
information is presented orally or sequentially, as in normal reading. As a
result, use of pictures, message boards, calculators, and other visual devices
may be helpful. Some children with Fragile X learn sign language, a visual
system. Computer software is now available for learning basic concepts in
language and math using high-interest visual themes.
Psychology
professionals warn against the tendency to assume that all characteristics of a
child with Fragile X stem directly from the Fragile X syndrome. The emotional
difficulties of an individual with Fragile X may include insecurity and anxiety
related to having a disability.
These
strategies are only a few that specialists have developed to help children with
Fragile X. Parents and other individuals working with these children should make
use of their assets, such as their positive outlook on life and love of other
people. Children with Fragile X should be encouraged to express their feelings
openly even when they have difficulty using words.
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Future
Research
Since the discovery of the Fragile X gene in 1991, there has been tremendous
progress in the understanding of this disorder. Preimplantation genetic
screening, using molecular genetic screening of in vitro fertilized embryos
followed by implantation of embryos that are free of the disorder, may be
available to would-be parents in the near future. Some affected families argue that not enough research is
being conducted on the treatment of Fragile X. In response, experts explain that
it is difficult to treat Fragile X without first understanding more about the
biology of the condition and the meaning of the DNA expansions. It has been
particularly difficult to investigate these questions in the absence of an
animal model. The nature of the Fragile X mutation may itself be a source of the
difficulty scientists are having in developing an animal model of the disease.
The excess genetic material of the Fragile X defect is so voluminous and so
fragile that inserting the Fragile X DNA into animal cells has been a problem
for laboratory scientists. However, there has been some recent progress in this
area, and continued research is likely to bring success.
Once
an animal model is developed, researchers will be able to learn more about the
basis of the Fragile X mutation and the mechanisms that contribute to its
unstable character. Ongoing analysis of the FMR-1 gene and its protein product
may help researchers understand the normal function of this protein and perhaps
find a way to intervene when its functioning goes awry.
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Sources
of Information
The
National Fragile X Foundation
PO Box 190488
San Francisco, CA 94119
510-763-6030
1-800-688-8765
Provides assistance and advice to parents and professionals, works to increase
awareness and encourage research.
Publishes
and sells brochures, information packets, a quarterly newsletter, and the
International Fragile X Directory that provides a list of Fragile X testing
sites, resource centers, and groups worldwide.
FRAXA
Research Foundation, Inc.
45 Pleasant Street
Newburyport, MA 01950
978-462-1866
FRAXA is a tax-exempt public charity, run by parents of children with Fragile X
syndrome. FRAXA's goal is to accelerate research aimed at the specific treatment
with Fragile X syndrome by direct funding of promising research projects and by
raising awareness of this disease.
March
of Dimes Resource Center
1275 Mamaroneck Avenue
White Plains, NY 10605
1-888-663-4637
This
document is copyright free. Readers are encouraged to copy and share it with
others. A publication of the National Institute for Child and Human and Human
Development (nichd). URL: http://www.nichd.nih.gov/default.htm
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