Fragile X Syndrome (Martin-Bell Syndrome)
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Introduction

So called as there is a ‘fragile site’ on the X chromosome. This is a non-staining, weakened section of the chromosome which is susceptible to breaking.
It is an example of a trinucleotide expansion mutation, but is usually inherited in an X-linked recessive pattern. 
Fragile X syndrome is the second most common cause of genetic learning difficulty after Down’s Syndrome.

Epidemiology

  • Affects 1 in 5000 males
  • The most common INHERITED cause of learning difficulty
  • Accounts for 4-8% of all male learning difficulty
  • Female carriers may show a mild form of the disease (in around 50% of cases)

Clinical features

Prominent Facial Features
  • High forehead
  • Large ears – often the most obvious sign
  • Long face
  • Prominent jaw

After Puberty

  • Large testes

Connective tissue signs

  • Hyperextensible joints
  • Stretch marks (striae)
  • Mitral valve prolapsed

Learning difficulties

  • Usually moderate to severe – often show autistic tendencies
  • IQ may be 20-80, mean of 50
  • May shoe hyperactive behaviour

In female cariers

  • Mild facial features may be present
  • May have reduced intellectual capacity
 

Cytogenetics

  • An example of a trinucleotide repeat expansion mutation
    • These mutation typically become more severe in successive generations
  • It is passed on in an X-linked recessive pattern
  • The fragile part of the chromosome is sometimes known as the FRAXA mutation. At this point there is a large CGG repeat sequence. In normal people, this sequence is 10 to 50 repeats long. In some individuals it is 50 to 200 repeats long. This makes this section unstable.
    • This type of instability as a result of repetition is known as premutation. The individuals are not affected, but have a high risk of having affected children.
    • In fragile X syndrome, the repeat is >200 repeats long.
  • The condition usually develops in the following manner:
    • A male with the premutation passes this on to all his daughters. Usually none of these patients will have clinical effects.
    • The female carriers are phenotypically unaffected now have a high risk of having a son with fragile X syndrome, as the repeat section is likely to be lengthened during meiosis. Any sequence of >100 repeats carries a high risk of having an affected child.
    • This is sometimes called expansion of the triplet sequence.
  • FRAXA is responsible for about 75% of cases of fragile X syndrome
  • FRAXE is another similar repeat sequence which is responsible for about 25% of cases of the syndrome. The repeat sequence is the same (CGG) but is in a different location on the chromosome.
    • FRAXE patients tend to have less severe learning difficulties
  • FRAXF is another similar site, however defects here do not appear to cause an clinical abnormality.
  • Symptoms are seen in:
    • Women with the full mutation – usually mild – about 50% of cases
    • All men with the full mutation
  • Never seen as a de novo mutation – and thus all mothers of affected children are carriers
  • As it is x-linked recessive:
    • All daughters of an affected male will be carriers
    • All sons of an affected male will be normal – fathers pass on the Y chromosome to their sons.

 

Genetic counseling for fragile X syndrome

  • The inheritance pattern is atypical x- linked.
  • As the condition is a major cause of learning difficulties, genetic counselling of affected individuals and carriers of the premutation is appropriate.
  • Women who carry the fully affected gene (>200 repeats)
    • 50% risk if her child is male
  • Women who carry the fully affected gene
    • 25% risk of having a daughter with learning difficulties
  • Chorionic villus sampling is able to tell if the defect is present
    • However, if the child is female, then the phenotype cannot be determined by this method

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Dr Tom Leach

Dr Tom Leach MBChB DCH EMCert(ACEM) FRACGP currently works as a GP and an Emergency Department CMO in Australia. He is also a Clinical Associate Lecturer at the Australian National University, and is studying for a Masters of Sports Medicine at the University of Queensland. After graduating from his medical degree at the University of Manchester in 2011, Tom completed his Foundation Training at Bolton Royal Hospital, before moving to Australia in 2013. He started almostadoctor whilst a third year medical student in 2009. Read full bio

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