Fragile X syndrome - an outline.

by Kathryn Milward ( July 2001 )



Fragile X Syndrome is an example of a triplet repeat expansion disorder. Other expansion disorders include Huntingdon’s disease and Spinal Muscular Atrophy. The most important clinical feature of Fragile X is that it causes moderate to severe mental retardation. It has a prevalence of 1 in 4000 and therefore is the second most common genetic cause of mental retardation after Down’s syndrome. Fragile X Syndrome is an X linked disorder therefore it mainly affects males, however females are affected although much less frequently and less severely.


Until recently fragile X syndrome was believed to have a prevalence of 1/1000. This is now thought to be an over-estimation, thanks to new accurate DNA analysis technologies we now believe that a prevalence of 1/4000 is much more likely. Until screening programmes are established allowing us to better diagnose patients we are unable to calculate an accurate prevalence. Fragile X Syndrome has been observed in all major ethnic groups.

Fragile X syndrome is extremely important as it accounts for approximately 50% of all X-linked mental retardation. Fragile X is the second most frequent genetic cause of mental retardation after Down’s syndrome.


The most important clinical feature seen in fragile X males is moderate to severe mental retardation and some studies have shown that the IQ of fragile X patients decreases with age.

Fragile X Syndrome also causes behavioural problems: - repetitive mannerisms, obsessional traits and autistic features are common amongst patients. Fragile X children are often hyperactive, unable to concentrate for short periods of time and unable to respond to simple instructions. Frequently they are also behind in speech and language development.

Many fragile X patients have certain characteristics associated with their facial appearance. Many sufferers have a high forehead, large ears, long face and a prominent jaw, most patients have a larger than normal head circumference. Many patients suffer from lazy eye and middle ear infections. Hyperextensible joints are often observed, for example double-jointed thumbs. Macro-orchidism (large testes) is seen in 74% of male patients after puberty.

These clinical features are generally not specific enough to allow easy diagnosis, because of this it is believed that not all sufferers of Fragile X syndrome are known to have the condition.


Originally Fragile X Syndrome was identified using cytogenetic studies. Cytogenetic studies involve looking at the structure and appearance of the chromosomes within the cells. By culturing the cells in a folate deficient culture medium the mutation causing fragile X can be observed in a small proportion of cells, however this technique is an expensive and fairly inaccurate means of diagnosis.

Modern DNA analysis techniques can now accurately detect the fragile X mutation and a laboratory test is available for diagnosis of Fragile X Syndrome.

At present there is discussion to whether or not we should screen for Fragile X Syndrome. The non-specific symptoms of Fragile X Syndrome make the condition difficult to diagnose, therefore it is likely many sufferers are not aware that they have the condition. By using screening programmes we could identify Fragile X sufferers and high risk individuals who would then be given the appropriate help and support. Through screening programmes we are likely to alter the attitudes of high risk individuals on topics such as reproductive behaviour, etc. It is for reasons like this that make it difficult to discuss the advantages, disadvantages, ethical issues and implications of screening programmes.


There is currently no direct medical treatment for Fragile X Syndrome. However we can improve the lives of sufferers through speech and language therapy, therapy for behavioural disorders and any direct symptomatic treatment.


Fragile X Syndrome is an example of a triplet repeat expansion disorder. The mutation that causes Fragile X Syndrome is located on the long arm of the X Chromosome at Xq27.3, near to an area of DNA known as a fragile site. A fragile site is a point in the DNA where the chromosome is more likely to break.

The mutation that causes Fragile X Syndrome is known as the FRAXA mutation. The area of DNA where the FRAXA mutation occurs is within a gene known as the Fragile X Mental Retardation Gene (FMR-1.)

In a normal person who does not suffer from Fragile X Syndrome, within the FMR-1 gene there is a region of trinucleotide CGG repeats. This means that the nucleotide sequence CGG is repeated a certain number of times, (CGGCGGCGGCGGCGG etc.) In a normal individual there are between 10 and 50 CGG repeats within the FMR-1 gene. These repeat sequences are stable and are unlikely to either increase or decrease in number between one generation and the next, this means that if your parents have 27 CGG repeats in the FMR-1 gene you are likely to have 27 CGG repeats in your FMR-1 gene. In a person suffering from Fragile X Syndrome there is an increase in the number of times the nucleotide sequence CGG is repeated and the repeat sequence is said to have expanded. A person suffering from Fragile X will have more than 200 CGG repeats within the FMR-1 gene, this is known as a full mutation.

How does this mutation cause Fragile X Syndrome?

The trinucleotide repeat sequence CGG in the FMR-1 gene is believed to have a function in regulating the FMR-1 gene. In a normal individual the FMR-1 gene is used to make a protein known as the Fragile X Mental Retardation Protein (FMRP). It is thought that the CGG repeat sequence is vital in the body’s ability to use the FMR-1 gene to make FMRP. When there are more than 200 repeats, as seen in Fragile X patients, molecular silencing occurs. This means that the body is unable to use the FMR-1 gene to make FMRP. It is believed that the symptoms and manifestations of Fragile X Syndrome are due to the body’s inability to make FMRP and therefore FMRP’s absence from the body.

In unaffected people the FMRP protein has been found in many cells of the body, especially in the brain and in the testes. Little is known about the function of FMRP but it is thought to have a function in binding RNA and therefore the production of certain proteins.

How is Fragile X Syndrome Inherited?

Fragile X Syndrome is an X linked disorder but shows unusual inheritance. Normal X linked disorders follow a certain pattern of inheritance.

Key Points,

Normal X Linked Recessive Inheritance –

X linked disorders are due to mutations on the X chromosome. Males only have one copy of the X chromosome (X,Y) while females have two copies (X,X.) If a female has a recessive mutation on one X chromosome they will not suffer from the disease as they still have another normal copy. However if males have a recessive mutation on the X chromosome they will suffer from the disease as they don’t have another normal copy.

Fragile X syndrome has unusual inheritance due to a permutation. As discussed above a normal person has between 10 and 50 repeat sequences and a person suffering from fragile X has more than 200 repeat sequences. If a person has between 50 and 200 repeat sequences they are said to have a premutation. If there are between 50 and 200 repeat sequences they are said to be unstable, this means that they are likely to change in number between generations.

The unusual inheritance of Fragile X Syndrome is illustrated in the following fictitious example: -

Fred has a premutation for Fragile X syndrome (between 50 and 200 CGG repeats in his FMR-1 gene.) As Fred only has a premutation he does not suffer from Fragile X syndrome and has normal intelligence. Fred only has one copy of the X chromosome, therefore when he has children all his daughters will inherit the premutation from Fred. Fred is known as a Normal Transmitting Male.

Fred has a daughter Julie. Julie inherits a normal X chromosome from her mother and the premutation for Fragile X on an X chromosome inherited from her father Fred. Julie will not suffer from any symptoms as she only has a premutation on one X chromosome and she has a normal X chromosome as well.

Julie decides to have children with Tom, a normal male. Julie and Tom have a boy, Jack, who is found to suffer from Fragile X syndrome. Jack will have inherited a normal Y chromosome from his father and a defective X chromosome from his mother. Premutations are very unstable and commonly a premutation will expand from between 50 and 200 repeats to over 200 repeats between one generation. Julie had a one in two chance of passing her defective X chromosome to Jack and due to the instability of the premutation Jack suffers from Fragile X because the number of triplet repeats increased between generations between mother and son.

Julie and Tom decide to have more children and have a daughter, Sarah. Sarah will have inherited a normal X chromosome from her father and a X chromosome from her mother and there is a one in two chance that the X chromosome Sarah inherits from her mother is defective. If Sarah inherits the defective X chromosome from her mother there is a chance that it may expand from a premutation to a full mutation (over 200 repeats) or it may remain as a premutation, either way Sarah remains normal as she has a normal copy of the X chromosome.

Other Information: Fragile X Syndrome in Females

Until now this page has discussed Fragile X Syndrome in males. Fragile X Syndrome is much more common in males than in females, however females can carry the full mutation and suffer from Fragile X Syndrome. In females Fragile X Syndrome is less severe. Most males with Fragile X will show moderate to severe mental retardation, however only about a third of female sufferers show any mental impairment.



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links updated on 2nd December 2002