Fragile X Syndrome

A Leading Cause of Mental Illness: Fragile X Syndrome

Heather Christensen

19 May 2011


Fragile X Syndrome is caused by a trinucleotide repeat of the CGG triplet pattern on an X chromosome. A repeat could range from a “gray zone” to a full mutation. Males are generally more affected than females due to having only one X chromosome. There are a variety of symptoms that can come from having Fragile X Syndrome including: prominent facial features, mental impairments, various developmental, speech, and behavioral problems. Two test’s are used to determine the diagnosis of Fragile X Syndrome prenatally, and two test's to determine the diagnosis of Fragile X Syndrome after birth. These test’s are the Chorionic Villus Sampling (CVS), Amniocentesis, Southern Blotting test, and PCR (Polymerase Chain Reaction). At this time there is no cure for Fragile X Syndrome, but the earlier the diagnosis, the better.


I have always had an interest in mental disabilities. With little known about specific disabilities, such as autism, I found it important to study a leading cause of these disabilities. I was watching “The Talk” one afternoon and the topic of autism came up because of it being Autism Awareness Month in April. As I was watching, the host and professionals kept saying that a lot is unknown about autism. This is when I began to search more about the topic. I was talking with my roommate after seeing the show, and she introduced me to Fragile X Syndrome.

Fragile X Syndrome is a recessive disorder that is said to be one of the most leading causes of autism and other developmental disabilities. It is caused by the lack of a protein, known as the FMRP. This protein is important in brain development. To make this protein, the FMR1 gene repeats itself in the normal range. If the repeat goes outside of the normal range the protein fails to be made, resulting in Fragile X Syndrome.

From the Time of Conception

To fully understand the effects of Fragile X Syndrome, it is important to look at the difference between a non sex-determining chromosome and a sex-determining chromosome. This is because Fragile X Syndrome effects the X chromosome on the 23 chromosome, the sex-determining chromosome. The determination of the sex of a baby is based on the separation of the male sex chromosomes, X and Y, during meiosis. In order for the successful transfer of genetic material from pairing and exchanging to occur, recombination or crossing-over needs to happen. The process of crossing-over results in the interlocking of homologous chromosomes and makes certain that the proper separation between the male chromosomes happens during the first meiotic cell division (Hawley, 870). According to Hawley, the process of recombination is distinctly different than the crossing-over of non-sex-determining chromosomes and play an important part in combining the Y chromosome into a successful meiotic program (870). In most instances, the pairing of homologous chromosomes and the initiation of recombination rely on the programmed introduction of double-stranded breaks in the DNA by the SPO11 protein. The pairing of the X and Y chromosome are found at the ends of the pseudoautosomal region. The difference between a sex-determining chromosome and the non-sex-determining chromosome is that the X and Y pairing is delayed significantly more than autosomes. The X and Y pairing are said to take place simultaneously with the delayed double-stranded breaks of the PAR (Pseudoautosomal) region, suggesting that this enables the pairing of the sex chromosomes. With this being said, the X and Y pairing and recombination occur in a small timeframe, unlike the rest of the genome (870-871).

An image of the chromosomes between a male and female.


What is Fragile X Syndrome and its Symptoms?

Fragile X is a recessive genetic disorder that is inherited through conception. Fragile X got its name because of the way it looks under a microscope. Under a microscope, the X chromosome seem to be “fragile” or “broken” (NFXF, 2011). It is estimated that 1 in 4,000 males and 1 in 6,000 to 8,000 females have Fragile X Syndrome (CDC, 2006). Also, around 1 in 800 males and 1 in 260 females are carriers of the premutation. Males are more susceptible to the syndrome because they only have one copy of an X chromosome. Because of this, if the male has the full mutation, they will have the syndrome. If males only inherit a normal or premutation, FMRP (Fragile X Mental Retardation) protein will still be made. Because females have two X chromosomes, it is not as common for them to have the syndrome. Females will have two copies of the FMR1 gene. If both X chromosomes have a stable FMR1 gene, they will produce FMRP. Females that have a premutation on one of their X chromosomes and have a stable FMR1 gene on the other, will still make FMRP. Females who have the full mutation on one of the X chromosomes and a stable FMR1 gene on the other, will produce a reduced amount of FMRP. It is not known exactly what the role of FMRP is, but evidence suggest that it is used for protein synthesis. What is known is that FMRP is important for survival, but is not needed. What they do know is that FMRP plays a role in cells, if that were not the case their would be no Fragile X Syndrome. If it played a large part in cells, people would not survive if they were missing the protein (NFXF, 2011).

Used with permission of
__**Rob Willemsen, Ph.D.**__, Erasmus University

A summarized table below shows the characteristics and symptoms of Fragile X Syndrome. As well as, the difference between a male and a female with Fragile X. The facial features tend to become more prominant with age. Children with Fragile X might also have learning disabilities, speech and language delays, and behavioral problems, such as ADHD. One of the differences between males and females that have Fragile X is the severity of their mental impairment. Males will generally have mild to severe intellectual disabilities, and females will have normal to some intellectual disability. This does not have to include a learning disability. Children with Fragile X Syndrome have a more frequent chance of having an Autism spectrum disorder (CDC, 2006).

Physical Features
(males and some females, except where noted)
Behavioral, Intellectual, and Social Characteristics
(toddlers, school age children and beyond)
Difficulties for Adults
(in addition to characteristics listed at left)
Issues Common in Females
including some carriers (females are usually less affected than males, but may have some of the features listed at left as well as these)
Important Family History Questions-
( positive family history increases possibility of Fragile X)
Large /protruding ears

Recurrent otitis media in childhood

Soft skin

Flexible joints ( particularly fingers, wrists, elbows)

Low muscle tone

Flat feet

Long face

Large testicles (males)
Seizure disorder
Speech and language delay
Motor delay (late crawling, walking, toileting)

Tactile defensiveness and sensory overload (high sensitivity to various fabrics/clothing, loud noises, crowds, food textures & tastes, etc.)

Hand-flapping, hand-biting


Poor eye contact/gaze aversion

Autism spectrum disorders
ADHD (attention deficit/hyperactive disorder)

Mental retardation, cognitive impairment or intellectual disability
Managing transitions to new schools, programs or employment

Learning adult living skills such as using transportation and money

Managing emotional upsets without aggressive behavior

Making and sustaining friendships
Visual-spatial challenges like reading maps and graphs

Executive functioning (the ability to formulate,
execute, and carry out a plan)

Shyness or social anxiety

Poor communication skills

Difficulty in picking up “social cues”

Anxiety, mood swings and depression
Family history of learning disabilities, mental impairment, including autism and other behavioral disorders

Family history of female relatives with infertility, early or premature menopause (symptoms in some females Fragile X carriers)

Family history of adults (particularly men) with late (after 50) onset neurological findings including intention tremor, ataxia, memory or cognitive decline, personality or psychiatric changes (symptoms in some older Fragile X carriers)

What Causes Fragile X Syndrome?

It is caused by a trinucleotide repeat disorder, a multiplication of part of the genetic information (NFXF, 2008). In some instances, like this one, mutations occur where significant numbers of bases are added to a gene (Tortora et al., 226). The mutation occurs in the FMR1 gene, near the 5′ end of the gene in the DNA that makes up the X chromosome (American College of Medical Genetics, 1994). The repeats occur in the exon region of the gene, at the beginning of the FMR1 gene (NFXF, 2008). In a healthy individual, there is a normal repeat of the FMR1 gene. The repeat is in the CGG triplet and repeated about thirty times. A person having a premutation, will have a repeat of 55-200 CGG triplet. Someone with the mutation will have 200-800 repeat triplet patterns (NFXF, 2008). An individual with 45-55 repeats will be in the “gray zone” (ACMG, 1994). Normally, the FMR1 gene produces an important protein called FMRP, which is important in brain development. When the gene is turned off, through mutation, the individual does not make the protein or only a little, causing the symptoms of Fragile X Syndrome (Eunice Kennedy Shriver NICHHD, 2010). Researcher's suggest that the cause of Fragile X Syndrome does not lie mostly with the repeat of CGG. Instead, it lies with methylation (NFXF, 2008). Methylation is the process where methylases, an enzyme, adds a methyl group to selected bases after a particular DNA strand is made (Tortora, 231). However, if CGG is repeated more than 230 times, it does set in motion methylation of the FMR1 gene. This methylation will stop the synthesis of the FMRP protein from being produced. leading to Fragile X Syndrome (NFXF, 2008).

external image gen7043.gif

Click here to view video about what causes fragile x syndrome:
(CDC, 2006).

What are the Tests to Determine Fragile X Syndrome?

Prenatal Test:

A test can be performed to determine if an unborn child has Fragile X Syndrome. This test is usually performed to someone who is a carrier of the syndrome. There are two tests used to determine if a fetus has the syndrome: Chorionic Villus Sampling (CVS) or Amniocentesis (NFXF, 2011). Chorionic Villus Sampling is taking an example of the Chorionic Villi cells, which have the same genetic DNA as a baby's cell from the placenta and taking a biopsy of the cells. The cells are then checked for problems (CVS, 2008). To determine what test to use, it depends on how far along the mother is in her pregnancy. Usually around ten weeks, the CVS test is performed. Between sixteen and twenty weeks, the amniocentesis test is performed.

After Birth:

Two methods in determining Fragile X Syndrome are used. These include a Southern Blotting Test and a Polymerase Chain Reaction (PCR) test. A PCR test uses primers to enlarge a fragment of the DNA that contains the repeats. The test shows the estimated number of repeats present in each allele. It allows the accurate size of the alleles in the normal, premutatioon, or the “grey zone”. A couple of downsides to PCR is that depending on the size of the mutation, it could be difficult to examine and produce a detectable product in the PCR assay.

A Southern Blotting test enables a view of the repeat segment and methylation status to be assayed at the same time. A methylation-sensitive restriction enzyme is used to cleave methylated sites to determine the difference between methylated and unmethylated alleles. A downside to Southern Blotting is that it is more labor intensive than PCR and needs more genomic DNA. It does not allow the exact size ranges of alleles, but will give an accurate size. Many labs have both test available, but will determine which one to use under the proper circumstances (ACMG, 1994).

What is the Cure for Fragile X Syndrome?

At this time there is no cure for Fragile X Syndrome. What can be done, however, is early treatment. The sooner a child with Fragile X Syndrome can get help, the better. A child’s brain is still developing when they are young, so they will have the best chances to develop their potential. The different treatments children can get are: appropriate education, behavioral or physical therapy, and medication (Eunice Kennedy Shriver NICHHD, 2006). Among these treatments there are others, such as, occupational therapy and medicines that help with aggression, anxiety, hyperactivity, and poor attention span. Although these tests are available, it is important to assess the person’s capacity and struggles to plan a treatment to fit their specific needs (NFXF, 2011).

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  6. Tortora, Gerard, Berdell Funke , and Christine Case. "Chapter 8, Microbial Genetics". Microbiology, An Introduction. 10th edition. San Francisco: Pearson Benjamin Cummings, 2010. 226. Print.

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