Fragile X Syndrome

by Randi Hagerman, M.D.
Professor of Pediatrics, University of Colorado Health Sciences Center
The Children’s Hospital
Denver, Colorado

What is fragile X syndrome?

Fragile X syndrome, also known as FXS, is a genetic disorder, which causes a wide
range of problems, from learning disabilities or attention deficits to more significant
developmental delays or mental retardation. Fragile X syndrome also can cause significant
emotional or behavioral problems, including anxiety, panic attacks, and hyperactivity
or Attention Deficit Hyperactivity Disorder (ADHD). Fragile X syndrome is the most
common cause of inherited mental retardation.


What causes fragile X syndrome?

Fragile X syndrome is caused by a mutation in the Fragile X Mental Retardation 1
gene (FMR1), which is located on the bottom end of the X chromosome. The FMR1 gene
produces a protein that is important for normal brain development. In studies, where
the X chromosome is viewed under the microscope, it narrows at the site of the mutation.
This narrowing makes the X chromosome look fragile, as if it would break, hence
the name, fragile X syndrome.

The mutation is made up of a repeat of the DNA nucleotide code, CGG. If you think
of DNA as a twisted ladder, the nucleotides represent the rungs on the ladder, and,
at the FMR1 gene, one side of the ladder has the repetitive CGG sequence. In normal
individuals, there are approximately 5 to 50 CGG repeats. In individuals who are
carriers of fragile X syndrome, but, usually, are not intellectually affected, the
CGG repeat is expanded from approximately 50 to 200 repeats. In individuals who
are significantly affected by fragile X syndrome, the CGG repetitions expand to
greater than 200, and, sometimes, up to 2,000. This is called the full mutation.

The full mutation undergoes a process of methylation, whereby a methyl group (CH3)
is placed on the backbone of the DNA, and the gene is “turned off.” Because the
gene is turned off, the protein it usually makes is not made. It is the absence-or
a deficiency-of the FMR1 protein that causes fragile X syndrome. Some individuals
may have cells with the premutation (50 to 200 CGG repeats) and other cells with
the full mutation (greater than 200 CGG repeats), so they produce a limited amount
of protein, and may be less affected than those individuals who have a full mutation.


Who gets fragile X syndrome?

Boys are more often affected by fragile X syndrome, because they have only one X
chromosome. Their other sex chromosome is Y, which makes them male. If they have
a full mutation on their X chromosome, they will be significantly affected by fragile
X syndrome. Girls, on the other hand, have two X chromosomes. If a full mutation
occurs on only one of them, then their other X chromosome will produce some FMR1
protein, if not a full amount. Thus, they will be less affected, as compared to
males. Usually, girls with the full mutation have learning disabilities or attention
deficit problems; although, in approximately 70% of cases, their IQ will be either
in the borderline range (70 to 85) or in the mildly retarded range (50 to 69).

Both males and females can be carriers of this disorder with the premutation. A
CGG expansion to the full mutation only occurs when a woman passes on this mutation
to the next generation. Therefore, all children who are affected with fragile X
syndrome have a mother who is a carrier. Because she has two X chromosomes (one
normal and one premutation), the carrier mother has a 50% chance of passing on the
mutation to each of her children. Fragile X syndrome usually affects multiple individuals
in a family tree; therefore, genetic counseling is important. A genetic counselor
will review the problems of all individuals in an extended family, and will talk
with family members who are at risk of being a carrier or affected by this disorder.


How does a FMR1 mutation cause disease?

The FMR1 mutation causes disease because the CGG expansion in the full mutation
range will turn off the gene, which, in turn, prevents the production of the FMR1
protein. The FMR1 protein controls the production of many other messages made by
cells in the central nervous system. The FMR1 protein is thought to be important
in determining that proper connections are made between nerve cells in early development.


What are the common findings?

Most children with fragile X syndrome have language delays, i.e., they may not speak
in phrases or sentences by 2 or 2 years of age. They also may be hyperactive, inattentive,
or impulsive early in childhood, which can lead to a diagnosis of ADHD. Children
with FXS are usually extra sensitive to stimuli in their environment, and they frequently
have tantrums or emotional outbursts in crowded situations or when making a transition
between activities. Shyness or social anxiety may be a common problem; however,
initially, many individuals may be shy, and, subsequently, they become impulsive
or talkative in social interactions.

Most children with FXS have changes in their connective tissue, such as soft skin,
“double-jointed” fingers and thumbs, prominent ears, or a long face. Large testicles
are commonly seen in boys with fragile X syndrome; however, this only begins to
occur in adolescence or just before the onset of puberty.

Many children may be diagnosed with autistic-like features, such as hand flapping,
hand biting, poor eye contact, repetitive speech, and sensitivity to being touched.
Approximately 15% of children with FXS also have a diagnosis of autism. These children
have more significant social deficits, in addition to shyness. However, most individuals
affected by FXS are interested in social interactions and are quite friendly.

Medical problems commonly associated with FXS include recurrent ear infections,
perhaps, because of looseness in the connective tissue. This problem is seen in
over 60% of cases, and often leads to the placement of pressure equalizing tubes
in the eardrums. Rarely, individuals with FXS may have hernias or joint dislocations.
Recurrent vomiting is a common problem at the time of birth, and, occasionally,
may persist into childhood. Seizures may occur in approximately 20% of patients.
Typically, seizures start in early childhood, are usually easily controlled with
medication, and often disappear by adolescence or adulthood. Eye problems may be
seen in up to 50% of children, including a lazy eye or a need for glasses.


How is fragile X syndrome diagnosed?

Fragile X syndrome can be diagnosed by two methods; both involve a blood test. The
first method is called cytogenetic testing. The white blood cells are grown in a
lab to show the fragile site on the bottom end of the X chromosome. Not every individual
affected by FXS will show the fragile site on the X chromosome. The second method
is called FMR1 DNA testing. This method costs approximately 0, which is less
expensive than cytogenetic testing. DNA testing will demonstrate the CGG repeat
number at the FMR1 gene. This test will diagnose all individuals affected by fragile
X syndrome. It also will identify those individuals who are carriers, which cytogenetic
testing does not. DNA testing is the best method of diagnosis. Your doctor can order
DNA testing or cytogenetic testing on your child, but all individuals who are suspected
of having the Fragile X chromosome should have a DNA test, even if cytogenetic testing
was previously performed. Rarely, an individual who is positive on cytogenetic testing
may be negative on DNA testing, meaning they do not have a mutation at the FMR1


How is fragile X syndrome treated?

All individuals who are affected by FXS require speech and language therapy and
occupational therapy, usually with a sensory integration approach. These therapies
stimulate and improve motor and language development. In children who have more
severe motor problems, treatment by a physical therapist also is necessary.

Most children affected by FXS also will require special education support in school,
including individual and/or group tutoring to help academic progress. Children with
FXS often have difficulty with math and, sometimes, spelling and reading. Most children
can be mainstreamed into a regular classroom; however, they may require an aide
to modify regular classroom assignments and to help them complete work.

Medications can be helpful for treating behavior and emotional problems. The use
of stimulant medication, such as methylphenidate (Ritalin) and dextroamphetamine
(Dexedrine or Adderall), are helpful for the majority of children with FXS who have
significant hyperactivity, short attention spans, or impulsive behavior. Usually,
these medications are tried at 5 years of age or older; although, occasionally,
they can be helpful in the preschool period. Clonidine or guanfacine (Tenex) are
medications that can reduce hyperactivity or overstimulation and improve tantrum
behavior. These medications can be used after age 3 and, sometimes, can be combined
with stimulant medication. The Selective Serotonin Reuptake Inhibitors (SSRIs),
such as Prozac, Zoloft, Paxil, or Luvox, can be helpful in treating anxiety, panic
attacks, obsessive compulsive behavior, or aggression and outburst behavior. These
medications can be used in childhood, adolescence, or adulthood. Sometimes, severe
behavioral problems may require the use of an atypical anti-psychotic drug, such
as risperidone; however, such a drug should be used in low doses, when necessary.

Medical therapy includes treating associated problems, such as recurrent ear infections.
These require the use of either preventive antibiotics or pressure equalizing tubes
to ensure that hearing is normalized and not damaged by continued infections. All
children with FXS should be seen by an eye doctor to rule out the possibility of
a weak eye muscle or the need for glasses, which occurs in approximately 30% to
50% of cases. If orthopedic problems occur, such as recurrent joint dislocations
or severe flat feet, an orthopedist should be seen. Severe flat feet may require
the use of a shoe insert or high top shoes with a firm arch to provide appropriate
support for the foot. Rarely, joint problems may require surgery.

A treatment program should include genetic counseling where parents can review the
family tree and determine who is at risk for being a carrier or being affected with
FXS. Siblings of a child with FXS should be tested for it with FMR1 DNA testing.
Genetic counseling is available to guide prenatal diagnostic procedures, which can
identify the degree of the mutation of the fetus at approximately 10 to 15 weeks
of pregnancy. Approximately 1 in 200 women in the general population is a carrier
of FXS, and approximately 1 in 2,000 women is affected by FXS.


What are the complications?

The complications of treating FXS include side effects from the medications that
are used. Higher doses of stimulant medication can cause weight loss, sleep disturbances,
or high blood pressure. Children who are treated with medications should see their
physicians at least 2 to 3 times per year to follow growth parameters and blood
pressure. Medications, such as clonidine or guanfacine, can cause significant sedation,
and also may require an EKG. The SSRIs can cause gastrointestinal disturbances or
diarrhea, which can be improved by adjusting the dosage or changing to a different
medication. Careful follow-up with us about side effects can lead to medication
changes and improved symptoms.


How is fragile X syndrome prevented?

It is possible to perform prenatal diagnostic testing for FXS using the FMR1 DNA
test. If the fetus is positive for the full mutation, the parents can elect to terminate
the pregnancy. Such decisions regarding termination or carrying on a pregnancy with
a fetus affected with FXS are very personal decisions. The family must make the
decision that is right for them. The genetic counselor and the physician will be
supportive of the family’s decision.


What research is being done?

A variety of research projects on fragile X syndrome are being conducted throughout
the world. A “knockout mouse model” has been developed where the FMR1 gene is missing.
These mice tend to be hyperactive and somewhat learning disabled on psychological
tasks. They also have large testicles and changes in their brain, which appear to
be similar to humans affected with FXS. The knockout mouse model may be helpful
for gene therapy research, where the gene is either replaced or protein is given
to the animal to relieve the symptoms. Research also is being conducted on how to
“turn on” the gene to produce the FMR1 protein in the nerve cells of FXS patients.
Gene replacement therapy or therapy to turn on the gene has not occurred in humans,
but it is occurring in test tubes and in animal models.

In addition, research is being performed to determine the best treatments, including
medication and educational and/or computer technology, to improve learning in those
individuals affected with FXS.


Links to additional information

The National Fragile X Foundation

P.O. Box 190488

San Francisco, CA 94119-0488

Phone: (800) 688-8765



FRAXA Research Foundation

P.O. Box 935

West Newbury, MA 01985-0935

Phone: (978) 462-1866




Reading for families

Fragile, Handle With Care: Understanding Fragile X Syndrome. Braden, M. (1997) Chapel
Hill: Avanta Publishing. (Can be obtained from The National Fragile X Foundation.)

Fragile X Syndrome: Diagnosis, Treatment and Research, 2nd edition. Hagerman, R.J.
and Cronister, A. (eds) (1996) Baltimore: The Johns Hopkins University Press.

Fragile X Syndrome. Hagerman, R.J. (1999) In: “Neurodevelopmental Disorders: Diagnosis
and Treatment.” New York: Oxford University Press, 61-132.

A Parent’s Guide to Drug Treatment of Fragile X Syndrome. Tranfaglia, M.R. (1996)
FRAXA Research Foundation, West Newbury, MA.

Transitioning “Special” Children Into Elementary School. Weber, J.D. Books Beyond
Borders, Inc., 1881 4th Street, #108, Boulder, CO 80302 (1-800-347-6440).


Reading for children

Boys With Fragile X Syndrome. O’Connor, R. (1995). (Can be obtained from the National
Fragile X Foundation.)

My Brother Has Fragile X Syndrome. Steiger, C. (1998) Chapel Hill: Avanta Publishing.

(Can be obtained by calling 1-800-434-0322.)


About the Author

Dr. Hagerman received her M.D. from Stanford Medical School and completed her pediatric
residency at Stanford and at the University of California San Diego. She is now
a Professor of Pediatrics at the University of Colorado Health Sciences Center and
Co-Section Head of Developmental and Behavioral Pediatrics.

Her research interests are in Fragile X Syndrome, Fetal Alcohol Syndrome, organic
causes of ADHD and behavioral phenotypes.

Copyright 2012 Randi Hagerman, M.D., All Rights Reserved