Fragile X Syndrome

                           Fragile X syndrome is a common genetic disease. This inherited form of mental retardation affects 1 in 4,000 males and 1 in 8,000 females (15). Males with fragile X often exhibit characteristic physical features and accompanying autistic and attention-deficit behaviors. Individual IQs are in the range 35–70 (16–18). Approximately 30% of females with full mutations are mentally retarded, and their level of retardation is, on average, less severe than that seen in males. 

                          In 1943, Martin and Bell (19) were able to link the cognitive disorder to an unidentified mode of X-linked inheritance. In 1967, Lubs (20) discovered excessive genetic material extending beyond the low arm of the X chromosome in affected males. Diagnosis was originally based on cytogenetic analysis of metaphase spreads, but less than 60% of the affected cells in affected individuals showed a positive result. With this variability in the test, the carrier status of individuals could not be determined. Interpretation of the result is further complicated by the presence of other fragile sites in the same region of the X chromosome. The fragile X gene (FMR1) is located in chromosomal band Xq27.3 and encodes an RNA-binding protein, which was initially characterized in 1991 (21–23) and contains a tandemly repeated trinucleotide sequence (CGG) end at its 5' end. 

                           The disease is caused by the absence of a functional FMR1 gene product (24). A small number of individuals classified as fragile X cytogentically have expansion at the nearby FRAXE locus, which also contains an unstable CGG repeat (25–28). The normal distribution of the repeat in the unaffected population varies from 6 to 50. Affected individuals are classified into one of two major groups; premutations of approx 50–200 repeats and full mutations with more than 200 repeats. Some alleles with approx 45–55 copies of the repeat are unstable and expand from generation to generation; others are stably inherited (29–31). 

                             The larger the size of the female premutation, the greater the risk of expansion during meiosis (32). Individual male or females carrying a premutation are unaffected (20,29,30). Males pass on the mutation relatively unchanged to all their daughters, all of whom are unaffected.