How do the Behaviors Seen in Persons with Fragile X Relate to Those Seen in Autism?

Many parents are confused about their child's diagnosis. On the one hand, they've been told
that their child has autism, "autistic spectrum disorder," or some degree of autistic-like
characteristics. In addition, they may have also been told that their child has fragile X
syndrome or that he or she is going to be tested for fragile X.

The association between autism and fragile X was first reported by Brown et al. (1982) and
was subsequently confirmed by many others leading to an extensive field of research. In
discussing this association it is important to remember that autism is defined behaviorally
using the criteria of the DSM IV manual which include lack of social reciprocity or
responsiveness, abnormal use of language and communication, and a restricted repertoire of
activities and interests. Autism is a heterogenous disorder which means that there are several
known causes of autism including phenylketonuria (PKU), tuberous sclerosis and 15q
duplications. However fragile X is the most common known cause of autism so far identified.
Autism is strongly genetic and it is likely that the inheritance of multiple genes predisposing
an individual to autism is necessary in many cases for the full behavioral syndrome to be
manifested.

The typical features of fragile X syndrome (FXS) i.e. hand biting, hand flapping, poor eye
contact, shyness, and social anxiety are probably related to the sensory hyperarousal that has
been documented by many investigators including Belser and Sudhalter (1995), Miller et al.
(1999), and Roberts et al.(2002). These features are often also referred to as autistic-like
features because they can be seen in individuals who have autism without fragile X. Most
children with fragile X, however, are interested in social interactions and do not meet the
diagnostic criteria for autism.

However, a subgroup of children with fragile X do meet diagnostic criteria for autism. Over
the last decade many studies have evaluated this issue and the percentage of children with
FXS who have autism has varied from 15 to 33%, mainly because the diagnostic criteria for
autism has varied and the diagnostic tools used have changed.

Recent work by Don Bailey and colleagues has found that in young boys with FXS, 25% met
the criteria for autism using the Childhood Autism Rating Scale (CARS) and that their profile
of behaviors was very similar to that of children with autism and without fragile X. They also
found that children with autism and FXS together, had a lower IQ than children with either
FXS alone or autism alone (Bailey, Hatton et al. 2001). Furthermore, the level of the fragile X
protein (FMRP) did not correlate with the presence or absence of autism. (Bailey, Hatton et
al. 2000) This suggests that autism with fragile X may relate to additional genetic or
environmental factors that could be additive to the FMR1 mutation.

Our studies also agree with this hypothesis. We recently reported a comparison study of
preschoolers with FXS, and age matched children (controls) with autism but without fragile
X and another set of children (controls) who had developmental disabilities but without
autism or FXS. (Rogers, Wehner et al. 2001) We evaluated all of these children with what are
the agreed gold standard diagnostic tools for autism including the Autism Diagnostic
Observation Schedule-Generic (ADOS-G) and the Autism Diagnostic Interview-Revised
(ADI-R) and also utilized the the DSM IV criteria, IQ and adaptive behavior measures.

We found that 15% to 33% of the children with FXS met the full criteria for autism. Their
profile of autistic features was indistinguishable from the children with autism without
FXS. Children with FXS who were not autistic had a behavioral profile that was similar to
the controls with developmental disabilities. In addition, the group with both FXS and autism
were the lowest of all the groups on developmental testing, results similar to the studies of
Bailey and colleagues.

The reason why some children with FXS have autism too, may relate to additional
background gene effects (other genes inherited from their mother and father) and further
studies are underway. There also are effects of the fragile X protein deficit that predispose
children to autism including the hyperarousal to stimuli and the shyness and social anxiety.
When these problems are severe in FXS, then autism is more likely to occur.

A recent report by Roberts et al. 2002 demonstrated more autonomic dysfunction (problems
with the sympathetic or parasympathetic nervous system such as increased heart rate when
scared or stressed) and hyperarousal in children with both FXS and autism compared to FXS
alone. Also of note is a recent neuroimaging study in females which demonstrated that the
size of the posterior cerebellar vermis (an area of the brain involved in motor function,
cognition and sensory perception) on MRI correlated inversely with the number of autistic
features. In addition, the number of autistic feature also correlated with the severity of anxiety
(Mazzocco, Kates et al. 1997).
More research is needed regarding treatment of children with both FXS and
autism. Preliminary studies in autism suggest that early treatment with a selective serotonin
reuptake inhibitor (medications like Prozac, Paxil, Luvox and others) is beneficial for both
language and socialization skills (DeLong, Teague et al. 1998) and this possibility needs to be
studied in children with FXS and autism. Intensive behavioral interventions are helpful in
young children with autism and this too needs to be evaluated in young children with FXS
and autism together (Scharfenaker, O'Connor et al. 2002).

Finally, it is important to identify the children with FXS among those who have been
diagnosed with autism alone to provide genetic counseling and access to treatments and
interventions known to be beneficial for individuals with FXS. Previous screening studies
have shown that 2.5% to 6% of boys with autism have FXS. (Brown, Jenkins et al. 1986;
Bailey, Phillips et al. 1996; Hagerman 2002) Therefore all children with autism and or mental
retardation should have fragile X DNA testing. Such screening may also identify individuals
with the fragile X premutation in association with autism and we are currently evaluating the
additive effect of the premutation which can be associated with mild gene dysfunction
(Tassone, Hagerman et al. 2000).
In summary, the association of fragile X syndrome and autism is a strong association which
requires assessment in each child and will guide future
treatment endeavors.

http://www.fragilex.org/html/autism.htm

FRAGILE X SYNDROME

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.

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.
(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.

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

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