FRAGILE X SYNDROME.

One day all mums-to-be will be offered carrier testing for Fragile X Syndrome.

What is Fragile X Syndrome

Fragile X syndrome is the second most common genetic cause of intellectual disability after downs syndrome.  The genetic mutation is situated on the X chromosome (Sex chromosome) so that males are more severely and more commonly affected than females.

Molecules called trinucleotides are normally repeated (duplicated) on genes. An increased number of trinucleotide repeats on the FMR1 gene of the X chromosome results in Fragile X Syndrome. The precise genetic mutation is not absolute. For example, up to 45 repeats is normal, and more than 200 repeats leads to fragile X syndrome, with a grey zone in-between called premutations. Therefore, the severity ranges from normal to severe.

Around 1 in 4000 males and  1 in 6000 females  have fragile X syndrome, with between 1 in 100 and 1 in 500 females having the premutation.

What are the symptoms of Fragile X Syndrome?

Features vary depending on whether male or female, and the precise mutation.

Males:

  1. Developmental Delay: Intellectual, Speech delay, motor delay and difficulty with coordination, and reduced muscle tone. However, IQ may also be normal.
  2. Behavioural: There may be attention deficit issues, speech disturbances, autistic-like features, aversion to sensory input (eg. aversion to touch or strong smells or bright light). Mental Health issues such as Increased anxiety.
  3. Physical characteristics which may be very subtle: High, Broad forehead, Long Face, Large ears, High arched palate (roof of mouth), and sometimes flat feet, loose joints or curved spine (scoliosis).
  4. Associated Medical Conditions: There may be occasional links with eye problems such as lazy eye, mitral valve prolapse, recurrent ear infections and up to a fifth have epilepsy.

Females with a full mutation usually have a milder form of the condition, and those with the premutation will probably not have any of the above features although the premutation has been associated with social anxiety.

Premutations can, however, cause:

  • Premature menopause (20% of permutation carriers develop the menopause under the age of 40) – this is a surprisingly common issue and may have issues with regards to genetic counselling.
  • A condition called fragile X tremor/ataxia syndrome (FTXTAS) that develops after the age of 50 and is commoner in males than females (around half of male carriers have the condition after the age of 70).

How is the diagnosis of Fragile X Syndrome made?

The diagnosis of may be considered when there is at least one of the features listed above and is confirmed by doing a fragile X DNA Test. The diagnosis in children will enable provision of appropriate health and educational services across a variety of different professionals depending on need.

Should I be tested if I have a family member with a fragile X mutation?

When a fragile X mutation is confirmed then there are issues for family members – potential issues for themselves, and their actual or future children.  Guidelines suggest that testing is carried out with both pre and post-test counselling.

The genetics and clinical implications of a positive result are often not straightforward although it is  fairly straightforward to rule out a fragile X mutation or permutation.

Summary

Fragile X is more severe in males than females and the full syndrome typically presents with developmental delay or learning difficulties or autistic features. A diagnosis can be made on a DNA test, lead to a proactive and co-ordinated approach to help the family and child and genetic counselling. Fewer mutations (premutations) may present only with premature menopause and this is becoming increasingly recognised.

WRITTEN BY: Dr Richard Beatty
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