Fragile X Info Series
Fragile X is a group of conditions associated with changes in the Fragile X gene — called “FMRl” and located on the X chromosome. The FMRl gene can undergo changes, when inherited, which affect a pattern of DNA called “CGG repeats.” Typically, the FMRl gene has up to 54 CGG repeats, though the range between 45 and 54 repeats, is called the “intermediate” or “gray zone.” A premutation carrier has 55–200 CGG repeats, and someone with a full mutation has more than 200 CGG repeats.
When a premutation or full mutation is present, it can result in a Fragile X-associated disorder (FXD). These include:
FRAGILE X SYNDROME
FXS is a condition affecting intellectual, behavioral, and social development. It occurs in both males and females who have a full mutation of the FMRl gene.
FRAGILE X-ASSOCIATED TREMOR/ATAXIA SYNDROME
FXTAS is an adult onset (over 50 years of age) neurological condition, seen in males and females, but more common and more severe in some male premutation carriers. It can cause tremors, memory, and balance issues.
FRAGILE X-ASSOCIATED PRIMARY OVARIAN INSUFFICIENCY
FXPOI is a condition affecting ovarian function that can lead to infertility and early menopause in some female premutation carriers.
OTHER PREMUTATION CONDITIONS
Other issues may be present in premutation carriers, and this is an ongoing area of study for researchers.
- The number of individuals in the U.S. who have or are at risk for a premutation-associated condition ranges from 1 in 151 females, or about 1 million women, to 1 in 468 males, or about 350,000 men.
- Among premutation carriers, about 40% of males older than 50 years and 8%–16% of women older than 40 years develop FXTAS.
- The risk of FXTAS in any given individual is influenced by their CGG repeat size (a larger number of repeats increases the risk), sex (men are at greater risk), and age (symptoms are more common at older ages).
- In women, the activation ratio, or percentage of cells expressing the premutation allele, may also play a role.
- The lifetime prevalence of FXTAS in the general population is estimated to be 1 in 8,000. This indicates that FXTAS is significantly less common than essential tremor or Parkinson’s disease in older adults.
Onset of FXTAS
- Typically, in the early seventh decade, with mean age of onset of tremor and/or ataxia in men at approximately 61 years.
- Symptoms of FXTAS vary among individuals. Typically, they include progressive signs of tremor, cerebellar ataxia, parkinsonism, and cognitive decline, with impairments in executive functioning.
- Tremor appears to be the sign most likely to trigger evaluation from a health provider.
Diagnosis of FXTAS
- FXTAS only occurs in individuals who have a Fragile X (FMRl) premutation. Therefore, it is essential that anyone being considered for this diagnosis is tested for and confirmed as a premutation carrier. (Also see Fragile X Info Series: Testing.)
- Neurological exam.
- Magnetic resonance imaging (MRI) findings consistent with FXTAS, such as specific white matter lesions in the brain or generalized brain atrophy.