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Fragile X Syndrome

Summary Sheet

What is fragile X syndrome?

Second most common genetic cause of learning disability (after Down syndrome)
o Patients often have special education needs
Most common inherited genetic cause of learning disability
Incidence: 1 in 4,000
Often associated with behaviour disturbance

Molecular basis
Name of condition derives from area on tip of X-chromosome that appeared
Fragile site on Xq27, specifically expanded CGG repeat on 5 UTR on the FMR-1 gene
(Fragile Mental Retardation Gene)
Unstable triplet repeat (CGG)
o Normal number: 25-30 repeats
o Premutation: 50-200 repeats
o Full mutation: >200 repeats

Mode of inheritance
Modified X-linked inheritance:
o Usually males affected
o Only carrier females have affected children
o Some female carriers affected
Premutation has strong tendency to become a full mutation when transmitted from
female carriers but not males
o Sons of female carriers: 50% chance of being affected
o Daughters of female carriers: 50% chance of being carriers
o Larger pre-mutations more likely to expand to full mutation

What would you expect to find on clinical examination of a patient with Fragile X syndrome?
Learning disability
30% of women with full mutation
Most affected males have mild-moderate learning disability
General inspection
o Delayed speech and language development
o Hyperactivity
o Anxiety
o Tall stature
Focused inspection
Hands: loose joints
Face: Large ears, with thickened earlobes, long face, prominent forehead
Feet: flat feet
Macro-orchidism (large testicles; seen in males post-puberty)

What would you expect to find on clinical examination of a patient who is a permutation
carrier for Fragile X syndrome?
Females: earlier menopause; premature ovarian failure
Males: late-onset progressive disabling ataxia (seen in 5-10%); tremor ataxia
syndrome (FXTAS)

What diagnostic investigations apply to Fragile X syndrome?

Targeted genetic testing e.g. Southern blotting or PCR

What are the clinical problems that can occur in people affected with Fragile X syndrome?
Attention deficit hyperactivity disorder (ADHD)

What are the key components of genetic counselling?

1. Comprehension of medical facts about a disorder and its managment
2. Understanding heredity and chance of recurrence
3. Explore impact on individuals and family