What is Fragile-X syndrome?

Genetics

• Fragile-X syndrome is caused by a mutation in a single gene, the Fragile-X mental retardation (FMR1) gene, which is located on the X chromosome.
• Normally, this gene contains a stretch of DNA in which a three base sequence (CGG) is repeated up to about 30 times in a row.
• In people with Fragile-X syndrome this three base sequence of DNA is repeated over 200 times. This abnormal repetition of bases creates the microscopic appearance of a gap on the long arm of the X chromosome (see illustration below), hence the name, ‘fragile’-X syndrome.

An illustration showing the appearance of normal and Fragile-X chromosomes.
Image credit: Genome Research Limited

Biology

• The FMR1 gene is responsible for providing instructions for making ‘Fragile-X mental retardation 1 protein’ (FMRP).
• This protein is required for the brain to develop normally. It plays a role in the development of synapses, specialised connections between our nerve cells which are critical for relaying nerve impulses.
• The Fragile-X mutation results in an FMR1 gene that is switched off, which means that FMRP is no longer produced, preventing normal neuronal development.
• Symptoms of Fragile-X syndrome are more severe in males compared with females. Because females have two X chromosomes, an inherited damaged FMR1 gene can be compensated for by an inherited healthy FMR1 gene. Unlike females, males only have one X chromosome, so an inherited damaged copy is their only copy.

Fragile X chromosome made visible by atomic force microscopy (AFM). The arrow indicates the fragile site.
Image credit: Dr Ben Oostra, Wellcome Images

Symptoms

• Fragile-X syndrome is the leading known genetic cause of autism (around 2-6 per cent of children with autism are diagnosed with Fragile-X syndrome).
• It is also the leading known cause of inherited intellectual disability.

Symptoms in boys

• Boys with Fragile-X syndrome have developmental delay, meaning they reach developmental milestones, such as sitting and talking, later than children without the condition.
• They show moderate to severe learning disabilities, combined with behavioural problems such as hyperactivity and autism.
• The physical signs of the disease become more pronounced as they get older. These include:
  • a characteristic long face with jutting jaw
  • large ears
  • high forehead
  • enlarged testicles
  • flat feet
  • unusually flexible finger joints.

Symptoms in girls

• Girls with Fragile-X syndrome have mild behavioural problems.
• 50 per cent of girls with the syndrome will show evidence of mental retardation.
• Like boys with the syndrome, girls tend to have large ears.

Diagnosis

• Testing for Fragile-X syndrome is recommended if:
  • one or more of the disease symptoms are evident in a child
  • the mother is known to carry a pre- or full mutation in the FMR1 gene. A pre-mutation is a FMR1 gene with 55 to 200 repeats of the CGG triplet. Women with the pre-mutation have an increased risk of having a child with Fragile-X syndrome.
  • if there is a history of unexplained mental retardation in the family.
• Testing is carried out by looking directly at the FMR1 gene in cells obtained from a blood sample. The number of repeated CGG triplets is counted within the FMR1 gene to identify if there are more than 200 repeats.
• Prenatal diagnosis testing is also possible to determine whether or not the baby has inherited the abnormal gene.

Treatment

• There is currently no cure for Fragile-X syndrome.
• Drugs can be used to prevent seizures and treat some of the common behavioural problems.
• Children with Fragile-X syndrome often benefit from specialist education including occupational and speech therapy.