Mutation of a gene on the long arm of the X chromosome is responsible for FXS and involves instability of trinucleotide repeat sequence. Normally there are 6 to 50 repeats, but with the mutation, the repetition sequence begins to expand and may increase from generation to generation eventually making this region unstable. When there are more than 200 repetitions, the fragile X mental retardation-I gene at Xq27.3 becomes hypermethylated and is inactive. This affects the gene product, the FMR-I protein, which is responsible to cause the physical, behavioral and cognitive aspects of the fragile X syndrome. A premutation carrier state exists when there are 50 to 200 repetitions of the CGG trinucleotide. The gene remains unmethylated in the premutation state and normal production of the FMR-I protein occurs.

Fragile X syndrome has an unusual inheritance pattern. There is no increase in repetition size with transmission of premutations from males to their daughters; daughters usually have similar premutation sizes and are not affected. The instability and expansion of the premutation occurs when females pass the gene on to the offspring.

The risk of expansion to a full mutation increases with the size of the premutation, as it expands from generation to generation. When the repeat size is greater than 90, the risk of expansion to a full mutation is almost 100 percent when a mother transmits the gene to her children.

DNA-analysis of the FMR-I gene is the best way to diagnose which is usually done on lymphocytes. Buccal smears can also be used.

• Individual seeking reproductive counseling who have a family history of fragile X syndrome or a family history of undiagnosed mental retardation.
  
  
• Prenatally, if mother known to be a carrier.
  
  
• Any child with
• Mental retardation
• Autism
• Hyperactivity in addition to a cognitive defect
• Language delay
• Previously diagnosed with Sotos' syndrome, Asperger's syndrome, and Pierre Robin sequence
• Selective mutism
• Schizotypal personality disorder
• Pervasive developmental disorder

FRAGILE X SYNDROME IN FEMALES:

The phenotype can vary from having no craniofacial features to having all features in males and variable intellectual involvement ranging from normal intellectual functioning to profound mental retardation.

For further details see Approach to case of Fragile X Syndrome

Last created on 23-02-2001
Last updated on 30-04-2007