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Fragile X

Fragile X Associated disorders are a family of three conditions:

  1. Fragile X Syndrome (FXS) is a genetic disorder caused by a mutation (a change in the DNA structure) in the X chromosome. It is the most common known cause of inherited developmental disability worldwide. One in 3,600 males and one in 4-6,000 females are affected. One in 150 females carry the premutation and will pass the gene on to 50% of their offspring, male or female, any of whom may be affected.
  2. Fragile X-associated tremor/ataxia syndrome (FXTAS), a condition which affects balance, tremor and memory in some older male gene carriers. More information: National Fragile X Foundation – FXTAS
  3. Fragile X-associated primary ovarian insufficiency (FXPOI), a problem with ovarian function which can lead to infertility and early menopause in some female gene carriers. More information: National Fragile X Foundation – FXPOI page

What is fragile x syndrome?

Fragile X Syndrome (FXS) is a genetic disorder caused by a mutation (a change in the DNA structure) in the X chromosome. It is the most common known cause of inherited developmental disability worldwide.

How common is it?

One in 2,500 males and one in 5,000 females are affected. One in 250 females carry the premutation and will pass the gene on to 50% of their offspring, male or female.

What is the cause?

The mutation causing FXS is found in the fragile X mental retardation 1 gene (FMR1). It involves the accidental lengthening of the normal gene, which disrupts its proper function. As you can see, below, the length of the gene is generally split up into four categories:

  • Normal: this category is considered to have no danger of having future generation affected with FXS. This group is not relevant in FXS.
  • Grey Zone: this group is not very well understood, but is thought to have no symptoms but have a slightly increased risk of having future generations with FXS.
  • Carrier (pre-mutation): Until recently, theyhave been considered asymptomatic. However, it has been found that some carriers can exhibit mild features such as learning difficulties and emotional problems. TheFXS-associated conditions are also found in a subset of carriers.
  • Affected (full mutation): Individuals with FXS (generally) have the longest FMR1 gene. Because the gene responsible for FXS is on the X chromosome, there appear to be more males, who have one copy, affected than females, who have two. However, it is important to note that females can be affected. Severity of FXS ranges from mild to severe, with some (although not always) correlation to gene length.

fx-gene

What are the clinical features?

Physical

Boys and girls may have prominent ears, high forehead, high palate, hyper-flexible joints, soft skin and flat feet. After puberty, the face may gradually become longer and boys may develop testicular enlargement. Medical complications do not generally develop, however, ear infections are common and there is an increased risk of epilepsy (seizures), strabismus (squint), mitral valve prolapse, hernia and joint dislocations. Physical features may not always be present, especially in children

Developmental

Intellectual disability occurs in 80% of males and 65% of females. Global problems tend to occur with learning disabilities and delays in speech, fine and gross motor movements and co-ordination difficulties.

Behavioural and emotional

Common features include attention deficit disorders with or without hyperactivity, anxiety (hyperarousal), extreme reaction or aversion to sensory stimuli (loud noise, touch, strong smells or tastes, eye contact) and difficulties with expressive language. Autism-like features include hand flapping and biting (or chewing on clothes), poor eye contact and resistance to changes in routine. A diagnosis of autism spectrum disorder, pervasive developmental delay or Aspergers may have been made. Girls may appear less affected and may present with shyness, social anxiety and moodiness.

A note on carriers:

  • A sub-group of carriers of the premutation may exhibit mild features of the full mutation including learning or emotional difficulties.
  • There is a higher risk of early menopause in females (Fragile X-associated primary ovarian insufficiency (FXPOI)) More information: National Fragile X Foundation – Menopause
  • Older males may develop a neurological disorder with hand tremour and balance problems (Fragile X-associated tremor/ataxia syndrome (FXTAS)) More information: National Fragile X Foundation – FXTAS

Weaknesses

  • Short-term memory
  • Auditory-only processing
  • Abstract concepts
  • Sequencing, praxis and planning
  • Fine and gross motor
  • Perceptual, visual motor
  • Social, language, semantic-pragmatic
  • Attention and initiation

Strengths

  • Learn visually eg pictures,computers
  • Whole word, number and pattern recognition, ‘gestalt’ learning
  • Long term and incidental memory
  • Concrete, relevant tasks
  • Strong imitation skills, drama
  • Good functional life skills
  • Friendly, good sense of humour

Treatments

  • Speech and language therapy
  • Occupational therapy with sensory integration
  • Special education
  • Psychological therapies
  • Medical and pharmacological

Strategies

  • Prepare for transitions with highly structured routines
  • Maximise visual input (use pictures, timetables)
  • Minimise auditory and visual distractions
  • Utilise calming strategies and distractors
  • Positively reinforce good behaviour

How is it diagnosed?

Families should visit their GP for referral to a geneticist or developmental paediatrician who can then arrange for a simple blood test. The test to request is “DNA studies for fragile X syndrome” although cytogenetic studies (“karyotyping”) should also be performed to exclude other genetic disorders. Testing should be done in combination with genetic and supportive counselling.

Who should be tested?

Testing should be considered for:

  • Any male or female with intellectual disability, developmental delay, learning disabilities, or autism-like features;
  • Individuals who have only had a cytogenetic test previously, or who were tested prior to 1991;
  • Pre-conceptual: women or their partners with a personal or an extended family history as above, or who wish to be tested;
  • Individuals with a confirmed family history of fragile X syndrome who could have inherited the mutant gene;
  • Obstetric: Pregnant women or their partners with a family history of fragile X syndrome, or intellectual disability of unknown cause; foetuses of a parent known to be a fragile X carrier; couples with a personal or family history of premature menopause; if undergoing IVF, CVS or amniocentesis.

Early detection allows the implementation of effective treatment and intervention strategies thus optimising outcome. As this is an inherited condition, diagnosis also allows families to make informed choices regarding both treatment and family planning.