Fragile-X syndrome 22/9/04. By Richard Twyman Fragile-X syndrome is an inherited form of mental retardation caused by a single malfunctioning gene on the X-chromosome.

Fragile-X syndrome is the commonest form of inherited mental retardation, affecting about one in 2000 males and one in 6000-8000 females in all ethnic groups. As well as learning and behavioural difficulties, affected individuals also tend to have a characteristic facial appearance with a prominent jaw and large ears. Some may suffer from seizures.

The symptoms are generally more severe in males than females. There is no cure for fragile-X syndrome, although drugs can be used to control the seizures and some of the behavioural problems. Affected individuals usually have a normal life span.

Genetics

Fragile-X syndrome is a single gene disorder caused by a malfunctioning gene on the X chromosome. The gene is named FMR1, which stands for fragile-X mental retardation, and is unusual in that it contains a stretch of DNA in which the same three bases are repeated over and over again.

See the FMR1 gene in the interactive chromosome browser [requires Flash].

In most people, the FMR1 gene contains fewer than 50 of these triplet repeats, allowing it to function normally. However, about one in every 200 women carries a larger number of repeats (50-200) which makes this section of DNA very unstable and liable to expand rapidly in the cells that will develop into eggs. Such women show no disease symptoms and are said to carry a pre-mutation, but they are likely to produce children carrying the full mutation, with 200 or more triplet repeats. In some way, this large number of repeats prevents the FMR1 gene from being expressed. The precise function of the gene is unknown, although it is thought to help nerve cells communicate with each other.

Symptoms

The symptoms of fragile-X syndrome are more severe in males than females because males have only one X chromosome, and therefore do not have a functional copy of the FMR1 gene to balance the effect of the mutated one.

Affected boys often reach developmental milestones such as sitting and talking later than their unaffected peers. They show moderate to severe mental retardation, often combined with behavioural problems such as hyperactivity and autism. As they grow older, physical signs of the disease become more pronounced: a characteristic long face with jutting jaw, large ears and high forehead; enlarged testicles; flat feet; unusually flexible finger joints.

Girls with the disease tend to have large ears and may suffer mild behavioural problems, but only about one-half of them show evidence of mental retardation.

Diagnosis

Testing for fragile-X syndrome is usually recommended if a child shows one or more of the disease symptoms, if the mother is known to carry a pre-mutation or a full mutation, or if there is a history of unexplained mental retardation in the family.

Originally, the test involved culturing cells under special conditions that would reveal a fragile site on the X chromosome, a site at which the chromosome was prone to breakage. This is how the disease got its name. However, this test is only effective in about 50 per cent of cases.

Now, testing is carried out by looking directly at the FMR1 gene in cells obtained from a blood sample, and counting the number of triplet repeats.

Treatment

While fragile-X syndrome cannot be cured, drugs can be used to prevent seizures and treat some of the common behavioural problems (for example, Ritalin is used to treat hyperactivity). Children with fragile-X syndrome benefit from specialist education, often including occupational and speech therapy.