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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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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 overstimulation. 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.
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.
Sources of information
The National Fragile X Foundation
PO Box 190488
San Francisco, CA 94119-0488
USA
Tel: 800-688-8765
Fax: 925-938-9315
E-Mail: NATLFX@FragileX.org
Internet: http://www.nichd.nih.gov/external.cfm?theurl=http://www.FragileX.org
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
Source: National Institutes of Health; National Institute of Child
Health and Human Development
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