Fragile X Syndrome

Fragile X syndrome is an inheritable genetic disease which causes multiple physical, psychological, and behavioral effects in both men and women. It is the leading cause of inherited mental retardation known today.

The disease is caused by the mutation of the FMR1 gene on the X chromosome. This gene encodes the Fragile X Mental Retardation Protein (FMRP), and in normal people, it is believed that the protein has some involvement in the regulation of protein synthesis. In some people, though, the gene gets mutated in the untranslated region of the gene just before the first exon (called the 5' UTR). Here, there are ordinarily a short series of CGG repeats in the DNA sequence, usually numbering between 7 and 52 in normal people. However, this region can be extended by recombination to number between 60 and 200 in the "premutated" gene (people with this gene do not have the disease, but their offspring are much more at risk of developing the disease), and upwards of 230 or more in the full mutation. It's also worth noting that already long sequences tend to elongate further between generations. When the number reaches above 200 or so, the DNA tends to be methylated at the CG junctions in this region; the methylation changes the accessibility of the DNA to certain proteins that would bind the DNA at certain points to promote transcription, thus turning off the gene. If the gene is not active, no protein is made; with no FMRP, several potential effects can be seen.

Effects/Symptoms of the Disease
It is worth noting that because the disease occurs on the X chromosome, men tend to have more pronounced symptoms of the disease. This is because women have two X chromosomes, one of which is most likely normal and will tend to counteract some of the negative effects of the disease.

• Physical Characteristics:
  • Facial Characteristics: long face, long ears, prominent ears, prominent jaw, enlarged head circumference
  • Characteristics due to Connective Tissue Alterations: double jointedness, ear infection due to improper draining of ear, mitral valve prolapse (heart murmur), flat feet
  • macroorchidism (enlargement of testicles) in men
  • early onset of puberty and/or menopause in some women
  Many of these symptoms do not manifest until after the onset of puberty.
• Psychological and/or Intellectual Characteristics:
  • Men tend to be cognitively delayed and exhibit signs of mild to profound mental retardation.
  • Women tend to be learning disabled, but most are on the borderline of mental retardation.
  • Sensory integration is often impaired. Fragile X patients tend to be hyperaroused, hypoaroused, hypersensitive, or incapable of integrating senses and motor reactions (hand-eye coordination).
• Behavioral Characteristics:
  • Attention deficit
  • inability to maintain eye contact
  • problems with speech, language
  • anxiety, especially when routine is disrupted (hypervigilance)
  • some symptoms of autism

People with fragile X syndrome are eligible for special education services under the Individuals with Disabilities Education Act, which provides for free public education that is suited to the person's needs.

Treatment of the disease usually includes genetic screening for parents and siblings of the affected person, medication for certain behavioral effects (when appropriate), and special education to encourage active participation in society. If you are concerned that you may be a carrier of the disease, contact your physician or a geneticist about a test.

Incidentally, the disease is called "fragile X" because the extended series of repeats and the methylation of the DNA prevent that region of the chromosome from coiling effectively. Thus, it tends to appear as though the tip of the chromosome is falling off, and in rare cases, the piece of DNA actually does separate from the rest of the chromosome.

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Excellent resources:
http://www.nfxf.org/ -- National Fragile X Foundation
http://www.nichd.nih.gov/publications/pubs/fragilextoc.htm