Fragile X Syndrome (FXS) is a rare, genetic neurodevelopmental disorder that affects approximately 1 in 4,000 males and females in the US. It is associated with highly variable cognitive and behavioral manifestations and has many overlapping features with ASD.
It is an X-linked disorder, meaning that the genetic mutation occurs on the X chromosome. In FXS, there is a trinucleotide repeat expansion in the FMR1 gene. A trinucleotide expansion is a particular type of gene mutation in which a sequence of three nucleotide base pairs improperly repeats itself multiple times. In the case of FXS, the repeating trinucleotide sequence is cytosine-guanine-guanine (CGG).
Normally, this DNA segment is repeated from 5 to about 40 times. In people with FXS, the segment is repeated more than 200 times. This typically results in no functional FMR1 mRNA transcript being produced, and the protein that is normally encoded by this transcript (fragile X mental retardation protein [FMRP]) is also absent.
FXS patients have the “full mutation” in the FMR1 gene (typically well over 200 CGG trinucleotide repeats), but patients with FXTAS are considered premutation "carriers" of the FMR1 gene, as they have CGG trinucleotide repeats numbering in the range of 55-200.
The job of the FMR1 gene is to make protein (FMRP) that is important in brain development.
Researchers believe that (for unknown reasons) having the premutation leads to the overproduction of FMR1 mRNA (which contains the expanded repeats). Researchers also suspect that the high levels of mRNA are what cause the signs and symptoms of FXTAS, but more research is needed to confirm these hypotheses.
Individuals with FXTAS usually experience symptoms after the age of 55. As premutation carriers age, especially men, the likelihood of experiencing symptoms rises. This likelihood reaches 75 percent by age 75 for premutation men.
The progression of symptoms, including memory loss, slowed speech, tremors, and a shuffling gait, is gradual, with interference of daily activities by tremors and falls occurring around ten years after onset of the first symptoms.
Dependence on a cane or walker occurs approximately 15 years after first exhibiting the symptoms of the disorder. Some people with FXTAS show a step-wise progression (i.e., symptoms plateau for a period of time but then suddenly get worse) with acute illnesses, major surgery, or other major life stressors causing symptoms to worsen more quickly.
The prevalence of FXTAS is unknown, although current estimates suggest that about 30%-40% of male FMR1 premutation carriers over 50 years of age, within families already known to have someone with Fragile X, will ultimately exhibit some features of FXTAS.