Fragile X syndrome

Definitions, genetics, and epidemiology Fragile X syndrome is the most frequent cause of familial mental retardation and the second most common overall cause of mental retardation after Down syndrome. The prevalence of fragile X syndrome has not been uniformly defined, but is estimated to be approximately 1 in 4000 in males and 1 in 8000 in females (Crawford et al. 2001). Fragile X syndrome comprises one-fourth to one-third of patients with X-linked mental retardation. Fragile X syndrome is an X-linked dominant disorder with reduced penetrance. It is named for the presence of an unstable chromosomal site on the long arm of chromosome X (Lubs 1969; Sutherland 1977). Typical fragile X syndrome is caused by a loss-of-function mutation of the gene FMR1, which is located at chromosome Xq27.3. The mutation leads to amplification of a CGG (cysteine-guanine-guanine) triplet nucleotide repeat in the 5′ untranslated region (exon 1) of FMR1. The result of this mutation is decreased or absent production of fragile X mental retardation protein (FMRP). There are three categories of CGG repeats: unaffected (6–54 repeats), premutation (55–200 repeats), and full mutation (>200 repeats) (Debacker and Kooy 2007). The CGG repeats that cause fragile X syndrome lead to transcriptional silencing of the FMR1 gene, which codes for FMRP; this is an RNA-binding protein that is expressed in a variety of tissues, but is most abundant in neurons. The presence of more than 200 CGG repeats leads to hypermethylation of the gene, causing reduced gene transcription, and thus a reduction or absence of FMRP synthesis.