Fragile X syndrome


Also known as: FXS
Last Review Date: March 15, 2016


What is it?

Fragile X syndrome is a genetic condition that causes a range of developmental problems including learning disabilities and intellectual impairment. It is the most common known cause of inherited intellectual and developmental disability affecting about 1 in 4000 males and between 1 in 5000 and 1 in 8000 females. It is also the most common genetic cause of autism. The syndrome is more often diagnosed in males than females, and males with Fragile X syndrome are usually more severely affected. According to the Fragile X Association of Australia, every week in Australia one child is born who is fully affected and 20 children are born who are carriers.

Fragile X syndrome is caused by mutations in the FMR1 gene. The FMR1 gene contains the DNA code to produce a protein, FMRP. This protein is present in a variety of tissues but is especially important in the brain. FMRP is essential for proper brain development and seems to play a role in ensuring that the connections between nerve cells (known as synapses) develop and function properly.

The FMR1 gene is carried on the X chromosome.  Males have one X chromosome and one Y chromosome whereas females have two X chromosomes. This means males have one copy of the FMR1 gene in each cell in their bodies whereas females have two copies of the gene in each cell.  In all women, one of the X chromosomes in each cell is randomly inactivated. If a woman is a carrier and has the FMR1 mutation on one of their X chromosomes, then on average, females will have about half of their FMR1 genes operating normally and as a result are affected less than males.

About 98 per cent of cases of Fragile X syndrome are due to mutations in a part of the FMR1 gene that contains a sequence of repeated groups of the three nucleotides CGG. These are known as triplet repeats. In most people the number of repeats is short (usually between 6 and 44 repeats) and this repeat length remains stable when passed from parents to children. However, in some people, the number of CGG repeats in the gene is increased and this is called a “repeat expansion”. Depending on how many repeats there are, the expansion is called a  “pre-mutation” if there are 55-200 CGG repeats, and a “full mutation”  if there are more than 200 CGG repeats present. Pre-mutations and full mutations affect the normal function of the gene and therefore, can have clinical consequences. 
 
Full mutation
Fragile X syndrome occurs when there is a full mutation in the FMR1 gene. Because they have only one X chromosome, men who have the full mutation in their FMR1 gene (more than 200 CGG repeats in the FMR1 gene) will have Fragile X syndrome. Women who have the full mutation in the FMR1 gene have less predictable outcomes. Because they have two x chromosomes, the random inactivation of only one X chromosome in each cell means some cells will have the faulty gene operating and some will have the normal gene operating. The result is that some women will be affected while others remain unaffected. About 50-60 per cent of women will have some degree of learning disability that can range from mild to severe.
 
Pre-mutation
People with a pre-mutation in the FMR1 gene do not usually have intellectual disability or the other characteristics of Fragile X syndrome, as enough FMRP protein is still being produced. Nevertheless, both male and female pre-mutation carriers are at risk of developing certain health problems later in life. They are at increased risk of developing a neurodegenerative disorder after middle-age called Fragile X tremor/ataxia syndrome (FXTAS). The lifetime risk of developing FXTAS is much higher for male pre-mutation carriers compared to female pre-mutation carriers. Women with pre-mutations also have about a 20 per cent risk of developing premature ovarian failure and having early menopause. (For more, see Symptoms.)
 


Symptoms

The Fragile X Association of Australia lists the following features that may be found in Fragile X syndrome:

Behavioural and emotional features
  • Anxiety and shyness
  • Attention Deficit Hyperactivity Disorder (ADHD)
  • Autistic type behaviours
  • Difficulty with eye contact
  • Tactile defensiveness
  • Repetitive speech
  • Aggression
Developmental features
  • Intellectual disability
  • Learning difficulties
  • Developmental delay
  • Speech and communication difficulties
  • Difficulty with coordination
  • Difficulty with fine and gross motor skills
Physical features
  • Physical features may be subtle or not present they can include
  • Low muscle tone and loose joints
  • Long narrow face, prominent ears (in older males)
  • High palate
  • Large testicles (in post pubescent males)
  • Mitral valve prolapse – heart murmur 

The way that Fragile X syndrome affects people varies. Girls and women, because they have two X chromosomes are usually less affected than boys and men, who have one X chromosome. A person affected by Fragile X syndrome may not show all of the signs described above. Children affected by Fragile X syndrome usually show some delay in language development apparent by age two.

People who are carriers of the pre-mutation in the FMR1 gene often have high levels of anxiety and a few children will show a milder version of the full syndrome including learning disabilities, attention deficit hyperactivity disorder (ADHD), autistic traits and other psychiatric manifestations. However, an alternative genetic cause for learning problems should always be sought in pre-mutation carriers, as the pre-mutation may not be the true cause.

About 20 per cent of women who are carriers of the pre-mutation may develop Fragile X-associated primary ovarian insufficiency (FXPOI) which causes premature ovarian failure and menopause before age 40. Others may not develop FXPOI, but may have infertility with or without regular menstrual cycles.
Men, and some women, with an FMR1 gene pre-mutation are at increased risk of developing a disorder known as Fragile X-associated tremor/ataxia syndrome (FXTAS).

The lifetime risk of developing FXTAS is much higher for male pre-mutation carriers compared to female pre-mutation carriers. Up to 40 per cent of men with the pre-mutation may develop symptoms of FXTAS after age 50 years. A much lower proportion of women with the pre-mutation will develop FXTAS. FXTAS causes slowly worsening movement problems and tremor that can sometimes be misdiagnosed as Parkinson’s disease. The main features of FXTAS are the development of problems with movement and loss of balance (ataxia) leading to falls, and tremor in the hands especially when trying to make voluntary movements. Other features may include memory loss, loss of feeling and burning sensations in the feet and behavioural changes including irritability and impulsive behaviour out of character with the person’s normal behaviour.
 


Tests

DNA testing for increases in the length of the CGG repeat area of the FMR1 gene is available. Testing is covered by Medicare when the person being tested has intellectual disability, ataxia, neurodegeneration, or premature ovarian failure which raises the possibility of an FMR1 pre-mutation or full mutation, or if the person has a relative with an FMR1 pre-mutation/full mutation.
 

Treatment

Currently there is no cure for Fragile X syndrome, but there are therapies that may improve quality of life and help a person reach their full potential. As there are sometimes associated medical problems including recurrent ear infections, joint problems, vision problems (including crossed eyes) and occasionally heart problems, medical interventions may be required. The best outcomes involve a multi-disciplinary approach to management which may include occupational, physical, psychological, special education and speech therapies. Early diagnosis is important as the sooner these interventions are started the better for the child. Genetic counselling in a genetic clinic is also recommended as there may be other family members at risk, including a future pregnancy of a couple who already have an affected child with Fragile X syndrome. There are reproductive options available for couples who already have a child affected with Fragile X syndrome, to avoid having another child born with Fragile X syndrome. These options include prenatal diagnosis (testing the pregnancy for Fragile X syndrome with a biopsy of the placenta or sampling of the amniotic fluid) or pre-implantation genetic diagnosis which involves IVF (in-vitro fertilization). These options are best discussed in a genetic clinic.
 

Related pages

On this site
Tests: FMR1 Mutations
Inside the lab: DNA Basics, Genetic Testing 

Elsewhere on the web 
CDC - Facts about Fragile X Syndrome (includes a video)
Fragile X Association of Australia
Genetics Home Reference – Fragile X syndrome
National Fragile X Syndrome Foundation (US)
NSW Health Genetics Education – Fragile X Syndrome