Fragile X Syndrome (Martin-Bell Syndrome)

Original article by Tom Leach | Last updated on 18/5/2014
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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