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.
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.
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.
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.
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.
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.
for Fragile X Carrier
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 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
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.
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
and Treating Fragile X Syndrome
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.
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.
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.
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
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
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.
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.
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.
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.
Language, and Learning Disabilities
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.
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.
of Children with Fragile X
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.)
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
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.
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.
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.
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.
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.
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.
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
National Fragile X Foundation
San Francisco, CA 94119
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.
Research Foundation, Inc.
45 Pleasant Street
Newburyport, MA 01950
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