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Fragile X syndrome

  • Fragile X syndrome is the most common cause of inherited learning disability after Down syndrome, affecting about 1 in 4,000 males.
  • It is an X-linked dominant condition (as female carriers can show signs of the condition). The pattern of inheritance can be complex because of the nature of the mutation that causes the condition.
  • Fragile X syndrome is caused by a mutation in the fragile X mental retardation 1 gene (FMR1) on the X chromosome.
  • The fragile X associated tremor/ataxia syndrome (FXTAS) occurs in males (and some females) who have a ‘premutation’ in the FMR1 gene. It is characterised by late-onset, progressive cerebellar ataxia and intention tremor.
  • About 20% of females who have a ‘premutation’ in the FMR1 gene develop premature ovarian failure, or POF (age at cessation of menses <40 years).

Clinical features

  • Moderate to severe learning difficulties in males with the condition and mild learning difficulties in some females who are carriers.
  • Behavioural problems, including autistic spectrum disorder, are common.
  • Signs of fragile X syndrome in early childhood are non-specific, making the diagnosis difficult.
  • In later childhood, affected males have a characteristic appearance with large head, long face, prominent forehead and chin, large protruding ears and large testes postpubertally.
  • Affected individuals have normal growth and stature, and no associated structural abnormalities of the brain or other congenital anomalies.

Diagnosis

  • A diagnosis of fragile X syndrome should be considered in boys who have moderate to severely delayed developmental milestones and in girls with mild delay, particularly when there is a positive family history of intellectual disability.
  • The diagnosis can usually be confirmed by DNA studies.

Genetic basis

  • Fragile X syndrome is an X-linked dominant condition. It is classified as an X-linked dominant condition because females who are carriers can show signs of the condition.
  • In >99% of individuals with fragile X syndrome, the mutation in the FMR1 gene is an amplified CGG triplet (trinucleotide) repeat. In people who do not have fragile X syndrome there are between 6 and 45 copies of the CGG triplet repeat at the start of the gene. Individuals with 55-200 of these repeats are said to have a ‘premutation’. People with the full mutation have more than 200 CGG repeats and will show features of fragile X syndrome.
  • There is also a grey or intermediate zone of 46-54 repeats, which can be difficult to interpret.
  • In females with the premutation, the repeats associated with the FMR1 gene can increase in number in the next generation to a full mutation.
  • All males with the full mutation will have fragile X syndrome. About 50% of females with the full mutation will have symptoms of fragile X syndrome but, in general, learning disability is much less severe than in males with the condition.
  • All mothers of individuals with an FMR1 full mutation are carriers of an FMR1 premutation
  • Mothers and their female relatives who are premutation carriers are not usually affected by fragile X syndrome, but are at increased risk for FXTAS (fragile X associated tremor/ataxia syndrome) and POF. All are at increased risk of having offspring with fragile X syndrome, FXTAS, and POF.
  • Males with premutations are at increased risk of developing FXTAS. A male with a premutation will not transmit it to his sons but will to all his daughters, who will be premutation carriers. The premutation may expand to a full mutation in the children of those daughters.

Clinical management

  • Early diagnosis enables early developmental interventions and appropriate educational placements.
  • Assessment of behavioural issues.
  • Treatment of medical problems.

Genetic testing

Genetic testing can be used to:

  • confirm the diagnosis in someone with possible fragile X syndrome (diagnostic testing);
  • provide information about the genetic status of the other relatives of an affected child; and
  • offer prenatal genetic diagnosis.

Genetic testing is widely available across the UK and usually provided through specialist clinics or regional genetic centres.

 

This information is intended for educational use and was current in August 2013. For clinical management, it is recommended that local guidelines and protocols are used.